Apparatus and methods for assisting breathing

ABSTRACT

The present invention provides, among other things, apparatus and methods of use for treating a subject in need of assistance with breathing. In some embodiments the subject suffers from airflow obstruction. In some embodiments, the subject suffers from chronic obstructive pulmonary disease.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application Ser.No. 61/436,010, filed on Jan. 25, 2011, which is incorporated herein byreference in its entirety.

BACKGROUND OF THE INVENTION

Disorders affecting the respiratory system are significant causes ofmorbidity and mortality. Chronic obstructive lung disease (COPD) is acommon disease whose prevalence is expected to rise considerably overthe next two decades. COPD can have debilitating effects on a patient'sdaily functioning and quality of life. Pharmacological therapies such asbronchodilators and corticosteroids are widely used in the treatment ofCOPD. A variety of non-pharmacological treatment modalities are alsoavailable. However, a significant proportion of patients experiencepersistent symptoms despite such interventions. There is a need forinnovative approaches to help manage COPD.

SUMMARY OF THE INVENTION

The invention provides, in some aspects, a method of treating a subjectcomprising: (a) sensing when a subject is exhaling; and (b) delivering astimulus to the subject's thorax or abdomen during at least part of theexpiratory phase of breathing in response to said sensing, so as toassist the subject with exhalation. In some embodiments the subjectsuffers from chronic obstructive pulmonary disease (COPD). In someembodiments the subject suffers from hyperinflation of the lungs. Insome embodiments performing the method decreases the subject's endexpiratory lung volume (EELV) as compared with the subject's EELV whenunassisted. In some embodiments the subject has an abnormally high EELVin the absence of the stimulus. In some embodiments the subject suffersfrom dynamic hyperinflation in the absence of the stimulus. In someembodiments, step (a) comprises detecting respiratory movement of thesubject's thorax or abdomen. In some embodiments, step (a) comprisesdetecting respiratory movement of the subject's thorax or abdomen usinginductive plethysmography. In some embodiments, step (a) comprisesdetecting respiratory movement of the subject's thorax or abdomen usinga strain gauge. In some embodiments the sensing is performed at least inpart using a sensor that is incorporated into an adhesive patch suitablefor placement on the subject's skin. In some embodiments the sensingoccurs externally to the subject. In some embodiments the stimulus isdelivered externally to the subject. In some embodiments the sensingoccurs externally to the subject and the stimulus is deliveredexternally to the subject. In some embodiments the sensor, device, orboth are incorporated into a garment or belt. In some embodiments thesensor and the device are incorporated into the same garment or belt. Insome embodiments step (b) comprises delivering electrical stimulation toone or more muscles of expiration and/or to efferent nerve(s) supplyingone or more muscles of expiration, wherein said stimulus is sufficientto cause contraction of said muscle(s) or increase the expiratory forcegenerated by said muscle(s). In some embodiments step (b) comprisesdelivering electrical stimulation to one or more abdominal muscles. Insome embodiments step (b) comprises delivering electrical stimulation tothe rectus abdominis muscle. In some embodiments step (b) comprisesdelivering electrical stimulation to one or more lower internalintercostal muscles of the anterior thorax. In some embodiments step (b)comprises mechanically compressing the subject's abdomen or loweranterior thorax. In some embodiments step (b) comprises mechanicallycompressing the subject's abdomen or lower anterior thorax using adevice comprising an inflatable compartment. In some embodiments thestimulus is not delivered while the subject is inhaling. In someembodiments a method comprises determining that the subject has at leastone sign or symptom indicative of an abnormally high EELV. In someembodiments a method comprises determining that the subject suffers fromCOPD. In some embodiments the stimulus is delivered near the onset ofexhalation, e.g., within 0.01 seconds and 0.25 seconds of the onset ofexhalation. In some embodiments a stimulus is delivered during some butnot all respiratory cycles within a session. In some embodiments amethod comprises analyzing a subject's breathing pattern or activitylevel and adjusting one or more stimulus parameters based at least inpart on the analysis. In some embodiments a subject is intubated or hasrecently been extubated.

In another aspect, the invention provides an apparatus comprising: (a) asensor suitable for detecting when a subject is exhaling; and (b) adevice adapted to deliver a stimulus to the subject's thorax or abdomenduring at least part of the expiratory phase of the subject's breathingin response to a signal generated by said sensor. In accordance withcertain embodiments of the invention, the stimulus is effective toassist the subject with exhalation. In some embodiments the stimulus isan electrical stimulus that stimulates one or more muscle(s) ofexpiration. In some embodiments, the device stimulates at least someabdominal muscles, e.g., the rectus abdominis muscle. In someembodiments, transcutaneous electrical stimulation is used. In someembodiments the stimulus is effective to assist the subject withexhalation. In some embodiments the stimulus is effective to result in adecrease in the subject's EELV as compared with the subject's EELVwithout the stimulus. In some embodiments the sensor comprises a straingauge. In some embodiments the sensor comprises a respiratory inductiveplethysmography sensor or piezoelectric sensor. In some embodiments thesensor is incorporated into an adhesive patch suitable for placement onthe subject's skin. In some embodiments the sensor is physicallyconnected to the device. In some embodiments the sensor is in wirelesscommunication with the device. In some embodiments the device comprisesmeans for delivering an electrical stimulus to one or more of thesubject's muscle(s) of expiration. In some embodiments the devicecomprises an abdominal muscle stimulator. In some embodiments theapparatus comprises a respiratory inductive plethysmography sensor orpiezoelectric sensor and an abdominal muscle stimulator. In someembodiments the device comprises means for mechanically compressing thelower anterior thorax or abdomen. In some embodiments the sensor, thedevice, or both, are integrated into a garment or belt. In someembodiments the sensor and the device are integrated into the samegarment or belt. In some embodiments the device comprises an inflatablecompartment that mechanically compresses the subject's lower anteriorthorax or abdomen when inflated. In some embodiments the apparatuscomprises a power supply. In some embodiments the power supply isattached to the device. In some embodiments the apparatus comprises acontrol unit that allows a subject to turn the device on or off. In someembodiments a control unit allows the apparatus to be set at any of twoor more modes. In some embodiments a control unit allows selection of astimulus protocol, one or more stimulus parameters, posture, and/orphysical activity. In some embodiments the apparatus comprises a sensor,a signal conditioning unit, a controller, and a stimulator. In someembodiments the apparatus comprises a controller that analyzes asubject's breathing pattern or activity level and adjusts one or morestimulus parameters based at least in part on the analysis. In someembodiments a method of treating a subject comprises providing thesubject with an apparatus of the present disclosure. In some aspects, amethod of making an apparatus comprises: (a) providing a sensor suitablefor sensing when a subject is exhaling; (b) providing a device adaptedto deliver a stimulus to a subject's thorax or abdomen wherein saidstimulus is effective to assist a subject with exhalation; and (c)linking the sensor and the device so that the sensor can communicatewith the device and cause it to deliver the stimulus during at leastpart of the expiratory phase of the subject's breathing. In someembodiments the apparatus comprises any of the components or featuresdescribed herein.

In some aspects, a method comprises: delivering an electrical stimulusto one or more of a subject's muscle(s) of expiration or to efferentnerve(s) supplying said muscle(s), so as to cause increased contractionof at least some of said muscle(s) selectively during the expiratoryphase of the subject's breathing. In some embodiments the methodcomprises: (a) sensing when a subject is exhaling; and (b) deliveringsaid stimulus so as to cause increased contraction of at least some ofsaid muscle(s) during at least part of the expiratory phase of thesubject's breathing. In some embodiments the stimulus is not deliveredwhile the subject is inhaling.

In some aspects, an apparatus comprises: (a) a sensor suitable fordetecting when a subject is exhaling; and (b) a device adapted todeliver an electrical stimulus to at least some of the subject's musclesof expiration during at least part of the expiratory phase of thesubject's breathing in response to a signal generated by said sensor,wherein the stimulus is effective to cause or increase contraction ofsaid muscle(s) during at least part of the expiratory phase of thesubject's breathing. In some embodiments the sensor comprises arespiratory inductive plethysmography sensor and the device is adaptedto deliver a stimulus to at least some of the subject's abdominalmuscles. In some embodiments the sensor, device, or both, are integratedinto a garment or belt. In some embodiments the sensor comprises apiezoelectric sensor and the device is adapted to deliver a stimulus toat least some of the subject's abdominal muscles. In some embodimentsthe sensor stimulates at least the rectus abdominis. In some embodimentsthe apparatus is capable of operating in two or more modes, wherein atleast one mode comprises delivering, in response to signals generated bysaid sensor, tactile stimuli that are sufficient to be felt by thesubject but are not effective to affect expiratory muscle contraction.In some embodiments timing of the tactile stimuli is selected so as toprompt the subject to exhale at least a specified volume or for at leasta specified time.

In some aspects, an apparatus comprises: (a) a sensor suitable fordetecting when a subject is exhaling; and (b) a device adapted todeliver an electrical stimulus to at least some of the subject's musclesof expiration during at least part of the expiratory phase of thesubject's breathing in response to a signal generated by said sensor,wherein the at least some of the stimuli are tactile stimuli, andwherein the timing of the tactile stimuli is selected so as to promptthe subject to exhale sufficiently to meet a target. In some embodimentsthe target comprises exhaling at least a specified volume or for atleast a specified period of time. In some embodiments the apparatuscomprises a controller that determines an appropriate stimulus, based atleast in part on analyzing the subject's breathing over one or morepreceding breathing cycles.

In some aspects the invention provides an abdominal muscle stimulatingbelt comprises a respiratory effort sensor. In some embodiments anabdominal muscle stimulating belt comprises a respiratory effort sensorcomprising a piezoelectric sensing element. In some embodiments therespiratory effort sensor is an integral part of the abdominal musclestimulating belt.

In some aspects, the invention provides a method of promoting increasedabdominal muscle strength in a subject, the method comprising: (a)sensing when a subject is inhaling; and (b) stimulating contraction ofat least one of the subject's expiratory muscles during at least part ofthe inhalatory phase of breathing in response to said sensing. In someembodiments the subject suffers from an obstructive respiratorydisorder.

In some aspects the invention provides a method of assisting breathingof a subject in need thereof, the method comprising steps of: (a)sensing when a subject is exhaling; and (b) delivering a tactilestimulus to the subject during at least part of the expiratory phase ofbreathing in response to said sensing, wherein the tactile stimulusserves as a cue to assist the subject with timing the contraction of thesubject's expiratory muscles. In some embodiments the subject has beeninstructed to continue exhaling or contracting the exhalatory muscleswhile he or she continues to feel the stimulus. In some embodiments themethod comprises determining an appropriate stimulus to be deliveredduring an exhalation, based at least in part on analyzing the subject'sbreathing over one or more preceding breathing cycles. In someembodiments the method comprises determining whether to deliver atactile stimulus or a stimulus that stimulates contraction of one ormore expiratory muscles during an exhalation, based at least in part onanalyzing the subject's breathing over one or more preceding breathingcycles. In some embodiments the subject suffers from COPD.

All articles, books, patent applications, patents, other publications,websites, and databases mentioned in this application are incorporatedherein by reference. In the event of a conflict between thespecification and any of the incorporated references the specification(including any amendments thereto) shall control. Unless otherwiseindicated, art-accepted meanings of terms and abbreviations are usedherein. The term “exhalation” is used interchangeably with “expiration”,“expiratory phase of breathing”, or “breathing out”. The term“inhalation” is used interchangeably with “inspiration”, “inspiratoryphase of breathing”, or “breathing in”. Section headings herein are forconvenience only and should not be understood to limit the invention.

Non-limiting information regarding risk factors, epidemiology,pathogenesis, diagnosis, and management of COPD may be found, e.g., in“Global Strategy for the Diagnosis, Management, and Prevention ofChronic Obstructive Pulmonary Disease” (updated 2009) available on theGlobal Initiative on Chronic Obstructive Pulmonary Disease, Inc. (GOLD)website (www.goldcopd.org), also referred to herein as the “GOLDReport”, the American Thoracic Society/European Respiratory SocietyGuidelines (2004) available on the ATS website atwww.thoracic.org/clinical/copd-guidelines/resources/copddoc.pdf,referred to herein as “ATC/ERS Guidelines” and standard textbooks ofinternal medicine such as Cecil Textbook of Medicine (20^(th) edition),Harrison's Principles of Internal Medicine (17^(th) edition), and/orstandard textbooks focusing on pulmonary medicine.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagram illustrating various lung volumes and capacitiesassociated with breathing. Definitions and information regarding methodsuseful for measuring these volumes and capacities are found, e.g., inthe ATS/ERS Task Force Standardisation of Lung Function Testing:Standardisation of the measurement of lung volumes (2005).

FIG. 2 is a graph that shows static respiratory volumes and capacitiesillustrative of a healthy adult human (left) and an adult human withCOPD (right). It will be understood that there is variability both amonghealthy individuals and persons with COPD.

FIG. 3 is a block diagram of an apparatus for providing electricalstimulation to expiratory muscles of a subject, e.g., in synchrony withexhalation.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

The present invention provides apparatus and methods of use forassisting the breathing of individuals suffering from obstructiverespiratory diseases. Obstructive respiratory diseases are disorders inwhich air flow limitation is a prominent and defining feature. Chronicobstructive pulmonary disease (COPD) encompasses a spectrum ofconditions characterized by airflow limitation that is not fullyreversible even with therapy and is usually progressive. Symptoms ofCOPD include dyspnea (breathlessness), decreased exercise tolerance,cough, sputum production, wheezing, and chest tightness. Persons withCOPD can experience episodes of acute (e.g., developing over course ofless than a week and often over the course of 24 hours or less)worsening of symptoms (termed COPD exacerbations) that can vary infrequency and duration and are associated with significant morbidity.They may be triggered by events such as respiratory infection, exposureto noxious particles, or may have an unknown etiology. Smoking is themost commonly encountered risk factor for COPD, and other inhalationalexposures can also contribute to development and progression of thedisease. The role of genetic factors in COPD is an area of activeresearch. A small percentage of COPD patients have a hereditarydeficiency of alpha-1 antitrypsin, a major circulating inhibitor ofserine proteases, and this deficiency can lead to a rapidly progressiveform of the disease.

Characteristic pathophysiologic features of COPD include narrowing ofand structural changes in the small airways and destruction of lungparenchyma (in particular around alveoli), most commonly due to chronicinflammation. The chronic airflow limitation observed in COPD typicallyinvolves a mixture of these factors, and their relative importance incontributing to airflow limitation and symptoms varies from person toperson. The term “emphysema” refers to enlargement of the air spaces(alveoli) distal to the terminal bronchioles, with destruction of theirwalls. It should be noted that the term “emphysema” is often usedclinically to refer to the medical condition associated with suchpathological changes. Some individuals with COPD have chronicbronchitis, which is defined in clinical terms as a cough with sputumproduction on most days for 3 months of a year, for 2 consecutive years.Asthma is another obstructive respiratory disorder, however theobstruction is usually (at least initially) reversible, i.e., withtherapy and/or between asthma “attacks” airflow through the airways ofpersons with asthma is typically normal, and thus these individuals donot have COPD. However, particularly if asthma is left untreated, thechronic inflammation associated with the disease can lead to airwayremodeling, causing the airway obstruction to become at least in partirreversible so that the asthmatic patient may then have abnormal airflow even between attacks. Thus asthmatic individuals with a fixedcomponent of airway obstruction are considered to have COPD.

The pathophysiologic changes that take place in COPD have a variety ofdeleterious effects on ventilation (movement of air into and out of thelungs) and the mechanics of breathing. Loss of alveolar walls andattachments to the small airways decreases lung elastic recoil.Decreased elastic recoil, together with airway narrowing, reduces theability of the airways to remain open during exhalation. Thus theairways tend to collapse earlier during exhalation. The collapse ofsmall airways during exhalation impedes airflow (sometimes referred toas “expiratory flow limitation” (EFL)), and as a result air becomestrapped in the lungs leading to lung hyperinflation. Hyperinflation isconsidered to be present when gas volume in the lung(s) is increased ascompared with the predicted value for age-matched, healthy individuals.In particular, patients with COPD have a significantly increasedend-expiratory lung volume as compared with healthy controls, which mayresult in an increased total lung capacity (TLC) (see FIG. 2). As knownin the art, “end expiratory lung volume” (EELV) (which term is usedinterchangeably herein with “functional residual capacity” (FRC)) refersto the volume of gas remaining in the lungs after passive expiration.EELV can be measured as known in the art, e.g., using the heliumdilution technique, single or multiple breath nitrogen washout test,body plethysmography, radiographic planimetry, CT scan, or othersuitable methods. The negative expiratory pressure (NEP) technique canbe used for the diagnosis or assessment of EFL. Using this method, thedegree of EFL present is evaluated by examining the proportion of theexpiratory phase over which airflow rate is unchanged when a smallnegative pressure is applied at the mouth. This technique has severalscales of measurement, including a 3 point scale, a 5 point scale, and acontinuous scale.

Tidal volume (TV) frequently remains relatively normal in persons withCOPD, but tidal breathing takes place at greater lung volumes thannormal (see FIG. 2) as a result of the increase in EELV. The residualvolume (RV), the volume of air left in the lungs following fullexpiration, is often increased in COPD, as is the total lung capacity,while the vital capacity remains relatively normal. Hyperinflation maybe reflected by various signs on physical examination, e.g., relativelyhorizontal ribs, “barrel-shaped” chest, protruding abdomen. Statichyperinflation refers to hyperinflation that occurs at rest and oftenbecomes more pronounced as COPD progresses. Dynamic hyperinflationrefers to acute and variable increase in hyperinflation (e.g., asreflected by EELV) above its baseline value and may occur, e.g., duringexercise and COPD exacerbations. It may be assessed by measuring theinspiratory capacity (IC).

COPD can lead to a variety of changes in the mechanics of breathing.Under normal physiologic conditions in healthy individuals, inspirationis an active process while expiration is passive during rest. Thediaphragm is the most important muscle of inspiration. It moves downwardupon contracting, forcing the contents of the abdomen downward andforward and causing the vertical dimension of the chest cavity toincrease. In addition, the ribs are lifted upwards and outwards causingthe rib cage to widen. The external intercostal muscles, which connectadjacent ribs, also function in inspiration by pulling the ribs upwardand forward, thus contributing to increasing the dimensions of thethorax. The increase in thoracic dimensions creates negative pressurewithin the lungs, resulting in air inflow. Due to their elasticity, inhealthy individuals under normal physiologic conditions the lung andchest wall return to their equilibrium positions after the expansionthat takes place during inspiration. Thus exhalation occurs passively.During exercise or other situations in which increased breathing isrequired, exhalation is an active process involving contraction of atleast some of the muscles of expiration, e.g., the internal intercostalmuscles, abdominal muscles (rectus abdominis, external oblique, internaloblique, thoracis abdominis). In persons with COPD, expirationincreasingly comes to depend on the expiratory muscles, particularly inthe end expiratory phase. In addition, the increase in EELV that occursin COPD requires the muscles of inspiration (diaphragm and externalintercostals) to operate at a higher volume than would otherwise be thecase. “Intrinsic” positive end-expiratory pressure (PEEPi), also calledauto PEEP, is often increased in persons with COPD and constitutes aninspiratory threshold load on the respiratory muscles, increasing workof breathing. Thus, for a variety of reasons, patients with COPD oftenexpend considerably more effort and energy in breathing than healthyindividuals.

The present invention encompasses the recognition that obstructiverespiratory diseases can be treated by applying a stimulus to the lowerthorax and/or the abdomen of a subject during the expiratory phase ofbreathing. Lower thorax refers to the region of the thorax at or belowthe 7^(th) intercostal space. In some aspects, the invention featuresdelivering a stimulus to the lower thorax and/or abdomen of a subjectwith an obstructive respiratory disease, wherein the stimulus iseffective to assist the subject with exhalation. In some aspects, theinvention provides a method comprising sensing when a subject (e.g., asubject with an obstructive respiratory disorder), is exhaling anddelivering a stimulus to the subject's lower thorax or abdomen based atleast in part on the sensing. In many embodiments, the stimulus isdelivered to the lower anterior thorax and/or to the abdomen. Inparticular embodiments, the stimulus is delivered to at least someabdominal muscles. In some aspects, the inventive method reduces thesubject's EELV. The invention provides a method comprises sensing when asubject (e.g., a subject with an obstructive respiratory disorder) isexhaling and delivering a stimulus to the subject. Thus the inventivemethod comprises delivering a stimulus “in synchrony” or “in phase” witha subject's exhalation based on sensing one or more indicators of thesubject's breathing. In some embodiments, the stimulus is effective toassist the subject with exhaling. In some embodiments the stimulus iseffective in training the expiratory muscles in order to gain strengthand endurance. In some embodiments a feedback system between a sensor(sensing when the patient is exhaling) and the muscle stimulationstimulus teaches the patient to use the proper muscles to assist inexpiration.

As described further herein, the invention also provides, in someaspects, apparatus suitable for use in one or more methods of theinvention. Thus in one aspect, the invention provides an apparatuscomprising: (a) a sensor suitable for detecting when a subject isexhaling; and (b) a device adapted to deliver a stimulus to thesubject's thorax or abdomen during at least part of the expiratory phaseof the subject's breathing in response to a signal generated by saidsensor. In some embodiments, the apparatus comprises a sensor and astimulus device that are integrated or readily integrable into a singleunit, such as a belt, that is wearable around the waist of a subject.Both (a) and/or (b) can be implantable or placed on the surface of theskin.

In some embodiments, the inventive method augments the natural action ofthe muscles of exhalation by stimulating them electrically ormagnetically or by delivering a mechanical stimulus to the loweranterior thorax and/or abdomen. In some embodiments, an electricalstimulus delivered to muscle(s) of expiration and/or to motor nerve(s)that supply those muscle(s) will increase the force of contractionduring expiration as compared with the force that would be generated inthe absence of the stimulus. The electrical stimulus may, for example,cause recruitment of a greater number of motor units of one or moreexpiratory muscles than would be stimulated as a result of a subject'stypical motor nerve impulse and/or cause contraction of one or moremuscle(s) or portion(s) of one or more muscle(s) that would otherwisenot substantially contract. Without wishing to be bound by any theory,in some embodiments an electrical stimulus may serve to automaticallystimulate muscles that are under voluntary control; thus the subjectwill not need to exert volitional control in order to cause suchmuscle(s) to contract. A mechanical stimulus can comprise mechanicalcompression of the lower anterior thorax and/or abdomen, causing anincrease in intrathoracic pressure and, in at least some embodiments,thereby assisting exhalation.

In some embodiments of the invention, the effect of the stimulus is toshift the volume at which tidal ventilation occurs downward. One aspectof the invention is the recognition that inhaling at lower lung volumesmay reduce stress on the muscles of inspiration, and thus a stimulusdelivered to muscles of exhalation has the potential to improveinspiration. For example, hyperinflation necessitates breathing overhigher ranges of the lung volume where the inspiratory muscles arefunctionally weaker. Hyperinflation depresses the dome of the diaphragm.In some aspects, use of an inventive apparatus reduces such depressionof the diaphragm. Use of an inventive apparatus may, by reducinghyperinflation, allow the fibers of inspiratory muscle(s), e.g., thediaphragm, to operate within a more optimal portion of theirlength-tension relation. The inventive method may reduce inspiratoryand/or expiratory muscle fatigue in patients with COPD. In patients withCOPD air trapping in the lungs increases greatly during exercise aspatients breath more rapidly, reducing the time available for exhalationand/or causing patients to start inhaling before full exhalation isachieved. The inventive method may reduce this dynamic hyperinflation,e.g., by causing air to exit the lungs more rapidly during at least partof exhalation than would otherwise be the case and/or by reducing thesubject's EELV that exists at the start of exercise.

A feature of certain aspects of the invention is that the stimulus(whether electrical or mechanical) is appropriately timed in relation tothe subject's natural expiration so as to result in one or more benefitsto the subject. Without limiting the invention in any way, the stimulusmay result in (a) a decreased EELV as compared with the subject's EELVin the absence of the stimulus and/or (b) an increased expiratory flowrate during at least a portion of exhalation than would be the case inthe absence of the stimulus. However, the stimulus preferably does notmake inhalation significantly more difficult for the subject. In atleast some embodiments, the stimulus does not increase the workassociated with inspiration and/or does not make inspiration feelsubjectively more difficult for the subject. In some embodiments, thestimulus actually makes inhalation easier for the subject, e.g., itreduces stress on at least some muscles during inhalation and/or makesinhalation feel subjectively easier for the subject. The inventivemethod, in some embodiments, avoids stimulating the muscles ofexpiration or mechanically compressing the anterior lower thorax orabdomen while the subject is inhaling (or any such stimulus is below thethreshold level required to produce significant muscle contraction orcompression during inhalation) and/or avoids significantly stimulatingthe muscles of inspiration while the subject is exhaling (or any suchstimulus is below the threshold level required to produce significantcontraction of the muscles of inspiration during exhalation). In manyembodiments, the muscles of inspiration are not stimulated during eitherexhalation or inspiration (or any such stimulus is below the thresholdlevel required to produce significant contraction of the muscles ofinspiration). However, as described herein, without wishing to be boundby any theory, the subject may benefit during inhalation as well. Theinventive method may or may not result in an alteration in the subject'saverage EELV as compared with the the subject's average EELV in theabsence of the stimulus. The inventive method may or may not result inan alteration in the subject's average TV as compared with the thesubject's average TV in the absence of the stimulus. The inventivemethod may or may not result in an alteration in the subject's averagerespiratory rate (RR). For example, some persons suffering from anobstructive lung disease such as COPD take frequent, shallow breaths inan effort to compensate for the condition. The inventive method mayrestore a more normal breathing pattern in such persons (e.g., higher TVand lower RR). In other persons suffering from an obstructive lungdisease, the average resting TV and RR may be approximately normal(normal resting TV is often estimated at about 500 ml and normal restingRR is often estimated at about 12-20 per minute, for adult humans), andthe inventive method may not significantly affect these values.

An inventive method may be applied for varying periods of time. Suchtime period may be referred to as a “session”. For example, and withoutlimitation, a session may last between about 30 minutes and about 12hours. In some embodiments, a session lasts between 1 and 6 hours. Insome embodiments, a session lasts for between 1 minute and 30 minutes.In some embodiments a session comprises multiple subsessions in whichstimuli effective to enhance expiratory muscle contraction are deliveredover a relatively short time period, e.g., from 1-5 or 5-10 minutes,alternating with time periods during which stimuli effective to enhanceexhalatory muscle contraction arc not delivered. The length and/ornumber of subsessions and/or time periods between subsessions mayindependently vary. As but one example, 6 subsessions, each lasting 5minutes, may be applied over a session lasting 1 hour, with 5 minuteperiods between subsessions. In some embodiments, the length and/ornumber of subsessions and/or time periods between subsessions arepredetermined prior to the beginning of a session. In some embodiments,the length and/or number of subsessions and/or time periods betweensubsessions are at least in part determined by the apparatus during asession based at least in part on input from a sensor that providesinformation regarding the subject's respiration or physical activity.Without limiting the invention in any way, it is noted that at leastsome beneficial effects may occur gradually after the stimulus has beenapplied over a number of breaths as, for example, trapped air is slowlyforced out of the lungs over a period of time. Thus one or more benefitsmay only become evident some time after a particular session has begun.Furthermore, without wishing to be bound by any theory, at least somebeneficial effects may last for a period of time after the stimulus isno longer being applied (i.e., after the end of a particular session).In other words, the subject may experience a period of continued benefitwithout continued application of the stimulus. In some embodiments,sessions are timed sufficiently close together that the subject'scondition remains at least somewhat improved during the time periodbetween sessions. It should be understood that the invention does notdepend on results achieved, which may reasonably be expected to varyamong different subjects.

The timing of delivery of the stimulus within the respiratory cycle andits characteristics, e.g., duration and strength, may vary. For example,one or more of these parameter(s) may be selected so that increasedcontraction of one or more muscle(s) of expiration or increasedcompression of the lower anterior thorax and/or abdomen will occurmainly during the first half or mainly during the second half of theexpiratory phase. In some embodiments, the stimulus is delivered duringeach respiratory cycle, while in other embodiments the stimulus may bedelivered less frequently, e.g., every second, third, fourth, or fifthbreath, or successive stimuli delivered according to a stimulus protocolmay be separated by different numbers of breaths. In some embodiments,stimulation is delivered between 12-20 times per minute, between 6-12times per minute, or between 3 and 6 times per minute. In someembodiments, the stimulus may be delivered substantially throughoutexhalation or during only a portion of the expiratory phase ofbreathing, e.g., during the first or second half of an exhalation. Insome embodiments the delivery of the stimulus begins a predeterminedamount of time after the end of inspiration or a predetermined amount oftime after the onset of exhalation. The stimulus may be delivered duringone or more time intervals during an exhalation, which time intervalsmay be separated by intervals in which the stimulus is not delivered.Furthermore, the magnitude of the stimulus may vary continuously ordiscretely during such time interval(s). Parameters can be selected,e.g., to optimize or enhance comfort and/or efficacy for a particularsubject or situation (e.g., exercise vs rest; awake vs asleep). In someembodiments, an electrical or magnetic stimulus is not delivered toexpiratory muscle(s) or to efferent nerves supplying them duringinspiration (or the magnitude of any electrical or magnetic stimulusdelivered during inspiration is not sufficient to cause contraction ofthe muscle(s) of expiration) and the lower anterior thorax and abdomenare not mechanically compressed during inspiration.

In some embodiments, the method comprises providing means by which anindividual can control at least aspects of the stimulus. For example, aninventive apparatus may have a control device that allows an individual(e.g., the subject, a caregiver, etc.) to switch the apparatus on or offand/or to select particular settings. The apparatus may have multiplepre-programmed settings that permit one or more parameter(s) orcombinations of parameters for the stimulus to be selected by anindividual based, e.g., on personal preference, comfort, therapeuticgoals, and/or activity level. Examples of situations in which differentstimulus parameters and/or signal conditioning procedures may be usedinclude, e.g., sleeping, quiet breathing while awake (e.g., in any ofvarious postures such as lying down, sitting, or standing), mildexercise that has a regular pattern (e.g., walking with few or nointerruptions), mild exercise that has an irregular pattern (e.g.,activities during which the subject starts and stops walking or moving,e.g., relatively often or at unpredictable times), etc. In some aspects,an apparatus or method disclosed herein selects stimulus parametersand/or signal conditioning procedures based at least in part a subject'sbreathing pattern, posture, and/or physical activity pattern. In someaspects, an apparatus or method disclosed herein applies stimulusparameters and/or signal conditioning procedures selected based at leastin part on a subject's breathing pattern, posture, and/or physicalactivity pattern. As described further below, in some embodiments anapparatus is capable of distinguishing between different breathingpatterns, postures, and/or physical activity patterns based at least inpart on input from one or more sensors. In some embodiments a methodcomprises distinguishing between different breathing patterns, postures,and/or physical activity patterns based at least in part on analyzinginput from one or more sensors and, in some embodiments, delivering anappropriate stimulus based at least in part on such analysis

The apparatus may be programmable so that parameters for delivering thestimulus can be customized for a particular subject and stored, so thata user will be able to conveniently select that combination ofparameters in the future. In some embodiments the apparatus comprisesmeans for receiving and/or responding to a voice input. For example, theapparatus may comprise or access voice recognition software. In someembodiments instructions (e.g., turning on and off, selecting aparticular stimulation protocol, etc.) may be given to the apparatus atleast in part orally.

The inventive apparatus and methods may be implemented using a varietyof different components, which may be combined in a variety of differentways. One aspect of the invention lies in the linking of variouscomponents (e.g., sensor, stimulus device), e.g., by means of anappropriate interface, so that the apparatus as a whole will function asdescribed herein. Appropriate electronics to interface a sensor suitablefor sensing when a subject is exhaling and a device for providing astimulus are an aspect of the invention. An interface may be implementedusing hardware, software, or a combination of hardware and software, andmay comprise analog and/or digital components. Appropriate signalprocessing and analysis functionality may be provided. An interface maycomprise one or more electronic components such as one or moreamplifiers, filters, rectifiers, peak detector(s), switches, analog todigital converter, connectors (e.g., DIN, XLR, etc.), wires, cables,etc. In some embodiments an apparatus comprises, e.g., as part of theinterface, a signal conditioning unit. In some embodiments a signalconditioning unit comprises one or more amplifiers and one or morefilters. Amplifier(s) may, for example, provide a signal amplificationgain of 1000 to 5000 in some embodiments. In some embodiments anapparatus comprises, e.g., as part of a signal conditioning unit, one ormore high pass filter(s) and/or one or more low pass filter(s). The highpass filter(s) may, for example, have a cut-off frequency in the regionof 0 Hz to 1 Hz. The low pass filter(s) may have, for example, a cut-offfrequency in the region of 10 Hz to 70 Hz. Such filter(s) may be of use,e.g., to eliminate or reduce noise or other artifacts. In someembodiments different signal conditioning procedures may be utilizedaccording to the setting. For example, different signal conditioningprocedures may be used to detect or eliminate movement artifacts if asubject is walking, breathing quietly while awake, sleeping, etc.

FIG. 3 shows an exemplary block diagram of an apparatus in certainembodiments. As depicted in FIG. 3, an exemplary apparatus comprisessensor 10, which provides an input to signal conditioning unit 20.Signal conditioning unit 20 processes the signal (e.g., usinginstrumentation such as an amplifier, filter(s), etc.). The processedsignal serves as input to controller 30. Controller 30 analyzes thesignal, determines whether and when to provide an output to electricalstimulator 40, and delivers an output to electrical stimulator 40 asappropriate. Electrical stimulator 40 generates an electrical stimuluswhich is delivered to a subject via electrode(s) 50. In some embodimentscontrol unit 30 receives additional inputs, such as from a user controlunit (not depicted in FIG. 3) or from one or more additional sensor(s)or signal conditioning unit(s) that process signals from such sensor(s)(not depicted in FIG. 3). For example, in some embodiments controller 30receives an input from a user control unit that selects one or morestimulus parameters or selects a particular stimulus protocol orstimulus mode. In some embodiments controller 30, in addition toproviding input to electrical stimulator 40, provides input to one ormore devices such as a computer, display, data storage unit, electronictransmission device, etc.

Materials, components, and parts for use in an apparatus of theinvention may be selected to provide a comfortable, relativelylight-weight, portable apparatus that can be used conveniently by asubject. In some embodiments, materials, components, and parts may beselected such that the total weight of the apparatus is less than orequal to about 0.5 kg-2 kg. In some embodiments, the apparatus iswearable and sufficiently light such that, in at least some embodiments,the subject can carry out most activities of daily living while usingthe device. In some embodiments, the apparatus is simple and convenientfor a subject to put on and use, so that the subject can employ theapparatus with minimal or no assistance.

In some embodiments, the apparatus of the invention collects, stores,analyzes, displays, and/or transmits physiological data from the subjectin addition to providing the exhalation sensing and stimulus deliveryfunctions described herein. The inventive apparatus may, in someembodiments, be used to sense various characteristics of the subject'sbreathing (in addition to the sensing required to determine when thesubject is exhaling) and/or to detect or measure other physiologicalvariable(s) or events such as heartbeat, blood pressure, oxygensaturation, temperature, etc. The apparatus may, for example, detect,collect, optionally analyze, store, and/or transmit, breathingfrequency, tidal volume, work of breathing, events such as coughing,and/or any other physiological variable(s) or event(s) of interest. Theinformation may, for example, be stored in the apparatus, downloaded toa computer or data storage device, and/or transmitted to a remotelocation (e.g., wirelessly) either directly by the apparatus or by saidcomputer. In some embodiments, technology used in the LifeShirt®(VivoMetrics; Ventura, Calif.) is used or modified for use in apparatusof the invention, e.g., for purposes of sensing, data collection, and/ordata transmission. The apparatus may provide useful monitoring ofhealth-related variables (e.g., cardiac parameters) in addition toassisting the subject with breathing. The remote location may be, e.g.,a facility where staff are available to assess the data and/or torespond to or initiate an alert, a data storage center, etc. Anelectronic transmission may occur over a communications network, e.g.,the Internet. In some embodiments a remote location is at least 1 kmaway.

A “computer” in the context of the present invention can be, e.g., asmartphone, personal digital assistant, personal computer (which may belaptop, desktop, notebook, or tablet computer), etc. Optionally, anapparatus of the invention interfaces with a computer that may compriseor be connected to a display, keyboard, mouse, or other peripherals.Optionally, information indicative of breathing and/or indicative ofoperation of an inventive apparatus can be visually displayed. Forexample, waveforms associated with breathing may be displayed and/orstimulus parameters may be displayed. In some embodiments, one or morelung volumes or capacities, work of breathing, respiratory movement oreffort reported by a sensor, and/or respiratory rate, or anyphysiological variable of interest, may be displayed. The invention thusprovides a system comprising any apparatus as described herein and acomputer that communicates with the apparatus either through a physicalconnection or wirelessly.

Non-limiting descriptions of exemplary materials, components, parts, andimplementation approaches that may be used in inventive apparatus and/ormethods are described herein, e.g., in the sections below. It should beunderstood that the invention encompasses use of different materials,components, parts, and/or means of implementation. Components, parts,materials, etc. may be freely combined in any reasonable combination,and the resulting apparatus and methods of use thereof are within thescope of the invention. In some aspects, the invention encompasses themodification of various components or parts, e.g., commerciallyavailable components or parts, to facilitate their use in an apparatusand/or method of the invention. Such modified components or parts areaspects of the invention.

Methods and Sensors for Sensing Exhalation

A variety of approaches and sensor types may be used to sense when asubject is exhaling. In general, a sensor of use in the presentinvention detects any of a variety of physical quantities that varyduring breathing and generates a signal, typically an electrical signal,indicative of the magnitude of the physical quantity and/or indicativeof a rate of change in the magnitude of the physical quantity. Thus thesensor may comprise a detecting or sensing element and a transducingelement, wherein the transducing element converts, e.g., mechanicalenergy into electrical energy and provides an output signal in the formof a voltage or current. Such element(s) may be located at least in partin a suitable housing, which may be composed, for example, at least inpart of a fabric, plastic, or other suitable material. The housing mayprovide means for attaching the sensor to a component of the apparatusor to a subject. In some embodiments the sensors may be implantable andsense one or more characteristics intracorporeally (for example bysensing intra-abdominal pressure). Implantable element(s) and/or theirhousing may be made at least in part of biocompatible materials suitablefor implantation. Descriptions herein of various modalities and sensorsavailable for sensing breathing are not intended to conflict with theunderstanding of those of ordinary skill in the art and should not beinterpreted to limit the invention.

In some embodiments of the invention, air flow is measured using, e.g.,one or more pressure and/or temperature sensors. For example, a thermalsensor (which may comprise a thermistor or pyroelectric material (e.g.,pyroelectric crystal)) generates a signal based on temperature changesdriven by the warm air of exhalation and the comparatively cool air ofinhalation passing over the sensor and can be used to determine when asubject is exhaling. A pressure-based airflow sensor generates a signalin response to changes in pressure produced by inhalation and exhalationand likewise can be used to determine when a subject is exhaling.Pressure and/or temperature sensors may be placed nasally or orally.

In some embodiments, a change in one or more dimension(s) of the thoraxor abdomen as an individual exhales and/or inhales is detected.Dimension(s) may include one or more of the three main dimensions of thechest: anteroposterior, transverse and vertical. Such measurements thuscan detect movement associated with inhalation/exhalation and/or changein volume of the thorax and/or abdomen that occurs with breathing. Asensor may comprise piezoelectric, optical waveguide, and/orelectroconductive materials. For example, the sensor may be apiezoelectric sensor that uses the piezoelectric effect to measurestrain or pressure and convert it to an electrical signal. Apiezoelectric sensor can be fabricated as known in the art using, e.g.,piezoelectric ceramics or single crystal materials. Such sensors may beused to measure air flow and/or respiratory movement. A piezo-electricsensor comprising a crystal outputs a signal when the crystal iscompressed or stretched, generating a voltage. In some embodiments, apiezoelectric sensor comprises a polymer with piezoelectric properties.The polymer may be provided as a film. For example, in some embodiments,polyvinylidene fluoride (PVDF), e.g., as a PVDF film, is used as asensing element in a piezoelectric sensor. In some embodiments apiezoelectric sensor represents changes in volume indirectly bycapturing strain in an elastic band or belt that is transferred to apiezo sensor. Such a belt or band is fastened around the chest orabdomen to measure changes in tension during breathing. Other types ofstrain gauges could be used as a sensor. Electroconductive fibers may beused as a sensing element, which may be incorporated intoelectroconductive strips or bands. In some embodiments, a change indimension(s) of the chest causes a change in the resistance of theelectroconductive strips or bands. In some embodiments, a change indimension(s) of the chest causes a change in inductance of theelectroconductive strips of bands.

Piezoelectric sensors that may be used for sensing breathing, andmaterials of use in such sensor(s) are described, e.g., in U.S. Pat. No.6,383,143; PCT application publication WO/2008/136980, and referencestherein. Piezo respiratory effort sensors and bands available fromPhilips Respironics (Murrysville, Pa.) or Scientific LaboratoryProducts, Ltd. (SLP) (St. Charles, Ill. and Tel-Aviv, Israel) orDymedix, Inc. (Shoreview, Minn.) may be used. For example, in someembodiments, the SleepSense™ Piezo Crystal Respiratory Effort Kit(product no. 1370) available from SLP or a PerfectFit™ Effort Beltavailable from Dymedix, Inc., or a P1420 or P1460 or similar Piezorespiratory effort sensor available from Philips Respironics is used.

Techniques for sensing breathing (and determining when a subject isexhaling) include inductive plethysmography and impedanceplethysmography. Inductance plethysmography comprises measurement basedon inductance or mutual inductance of conductive elements placed arounda body part of a subject, e.g., around a subject's chest and/or abdomen.Respiratory inductive plethysmography (RIP) in some aspects of theinvention utilizes the principle that a changing (e.g., oscillating)current applied through loops of wire generates a magnetic field.Appropriate wires arc placed around the subject's chest and/or abdomen(often about both the chest and abdomen) and a signal is sent throughthe wires. One or more characteristics of the signal (e.g., itsfrequency) is altered as a result of the movements of breathing as theychange the area enclosed the wires. The alteration in the signal isrepresentational of the change in area that occurs with breathing andcan be used to determine, among other things, when a subject isexhaling. A RIP sensor can, for example, generate a signal representingchanges in tidal volume over time. A plateau in TV or beginning of adecrease in TV occurs as exhalation begins. RIP sensors are well knownin the art. See, e.g., U.S. Pat. Nos. 5,131,399; 5,913,830; PCTapplication publications WO/2001/003581; WO/2006/03429, etc. The wiresof a RIP sensor are typically contained within belts or bands, in someembodiments, encircle the rib cage and abdomen at about the level of thenipples and the umbilicus. The bands or belts may be between about 1-5cm wide in certain embodiments. They may at least in part be composed ofa stretchable material or may comprise a section composed of astretchable material to permit close fitting. In some embodiments, a RIPsensor comprises two sinusoid wire coils insulated and placed within twoapproximately 2.5 cm (about 1 inch) wide, lightweight elastic and,optionally, adhesive bands. The transducer bands are placed around therib cage under the armpits and around the abdomen at the level of theumbilicus. They are connected to an oscillator and subsequent frequencydemodulation electronics to obtain digital waveforms. During inspirationthe cross-sectional area of the rib cage and abdomen increases, alteringthe self-inductance of the coils and the frequency of their oscillation,with the increase in cross-sectional area proportional to lung volumes.The electronics convert this change in frequency to a digitalrespiration waveform where the amplitude of the waveform is proportionalto the inspired breath volume.

RIP sensors available from Philips Respironics or Scientific LaboratoryProducts (SLP) may be used in the inventive apparatus. For example, zRIPDuraBelt inductance respiratory effort sensors (Philips Respironics) orSleepSense® sensors (SLP) may be used.

In some embodiments of the invention, position sensor feedback is used,e.g., to adjust calibration of a respiratory sensor, e.g., an RIPsensor, e.g., after the subject changes position.

In some embodiments, impedance plethysmography is used to sense when asubject is exhaling.

The apparatus can comprise multiple sensors (e.g., 2, 3, 4, 5, or more),which can be of the same or different types (e.g., RIP andpiezoelectric). The signals generated by the multiple sensors may beanalyzed to improve the accuracy of determining when a subject isexhaling (as compared with the accuracy obtained with a single sensor).For example, in some embodiments multiple sensor(s) must generate asignal indicative of exhalation in order to trigger delivery of thestimulus.

In some embodiments, a sensor is equipped with means that permitintegration with or reversible attachment to a garment or belt.

In certain embodiments, one or more implanted sensor(s) is used. Thesensor(s) may directly detect action potentials or muscle contractionsin some embodiments.

It should be understood that “sensing when a subject is exhaling” isused in a broad sense to encompass any appropriate method of determiningan appropriate time to deliver the stimulus (e.g., within a particularrespiratory cycle consisting of an inhalation and an exhalation), e.g.,so as to assist at least with exhalation. In some embodiments, theapparatus senses the onset of exhalation. For example, a change frominhaling to exhaling may be detected by detecting a change from inwardto outward flow of air and/or by detecting that one or more dimensionsof the thorax that had been increasing has reached a plateau or isdecreasing. It will be appreciated that the event(s) or phenomena thatare detected to determine when a subject is exhaling may occur duringinspiration. For example, as inspiration comes to an end during eachbreath, the inspiratory flow rate and rate of expansion of the thoraxtypically decline. A decline in inspiratory flow rate and/or rate ofexpansion of the thorax may be detected and serve as a means todetermine that the expiratory phase of breathing will occur within ashort time thereafter. It will also be understood that the differentsensing modalities may not produce identical results, e.g., as comparedwith results that would be obtained using spirometry. The inventionencompasses variations in the absolute timing of delivery of thestimulus that would result from use of different sensing modalities,e.g., as compared with the timing that would result if spirometry wereused to determine when a subject is exhaling.

Electric or Magnetic Stimulus and Stimulus Device

In some embodiments, the apparatus delivers an electric or magneticstimulus to at least some of the expiratory muscles so as to elicitmuscle contraction. Expiratory muscles of interest include the rectusabdominis, external oblique, internal oblique, and transversusabdominis. (It will be understood that an electrical or magneticstimulus may be delivered to a portion of one or more muscle(s). Inother words, the stimulus may be applied only to a portion of a muscleor muscle(s) rather than the entire muscle.)

In some embodiments, the device employs electrical muscle stimulation,which is well known in the art. EMS elicits muscle contraction usingelectric impulses. The impulses are generated by the device anddelivered through electrodes positioned in close proximity to themuscle(s) to be stimulated and/or in close proximity to efferentnerve(s) that supply such muscle(s). For example, the electrodes may bepositioned on the skin and may directly overly the muscle(s) to bestimulated. The device causes muscles to contract (typically repeatedly)by applying pulsed electric current through the cutaneous electrodes.EMS is used for various purposes such as in physical rehabilitationafter injury, pain management, and in sports training. EMS devices areavailable, e.g., from Compex Technologies, Inc. (New Brighton, Minn.)(now owned by DJO, Inc., Vista, Calif.), and such machines may be usedto deliver a stimulus to at least one muscle of expiration in variousembodiments of the invention.

In some embodiments, a stimulus is delivered to at least one abdominalmuscle. Abdominal muscles of main interest in various embodiments of theinstant invention are the rectus abdominis muscle, the external oblique,the internal oblique, and the transversus abdominis. The rectusabdominis muscle is a paired muscle running vertically on each side ofthe anterior wall of the human abdomen (and in some other animals). Theexternal oblique muscle (also external abdominal oblique muscle) is thelargest and the most superficial (outermost) of the three flat musclesof the lateral anterior abdomen. The internal oblique muscle is theintermediate muscle of the abdomen, lying just underneath the externaloblique and just above (superficial to) the transverse abdominal muscle.The transversus abdominis muscle is a muscle layer of the anterior andlateral abdominal wall which is deep to (layered below) the internaloblique muscle. Nerves supplying one or more abdominal muscles includethe inferior five intercostal, subcostal, and iliohypogastric nerves.

The number, shape, and position of the electrodes can vary and may beselected by one of skill in the art. For example, in some embodiments,between 2 and 16 electrodes may be used. In some embodiments, between 3and 8 electrodes are used. The electrodes may be substantially square,rectangular, circular, or have other shapes. Exemplary lengths of theside(s) of a rectangular electrode may range, e.g., from about 4 cm-16cm. In some embodiments, at least some of the electrodes are elongatedstrip-like shape (e.g., about 2-4 cm wide and about 12-20 cm long). Theposition of one or more of the stimulating electrodes may be selected soas to predominantly stimulate, e.g., the rectus abdominis muscle, orportion(s) thereof. In some embodiments, the rectus abdominis andexternal oblique muscles are stimulated. In some embodiments, electrodesare positioned on the abdomen under the costal margin and above thesymphysis bone. Electrodes may be positioned approximately symmetricallyaround the midline. In some embodiments, a single electrode ispositioned approximately on the mid-line, and one or more electrodes areapproximately symmetrically placed on each side of the midline (e.g.,one on each side). In some embodiments, an electrode or arrangement ofelectrodes may be approximately V-shaped and symmetrically positionedabout the subject's midline with the apex pointing downwards. In someembodiments, or more pairs of elongated, strip-like electrodes may, forexample, be placed so that they run diagonally downwards under costalmargin on each side of the midline. In some embodiments, electrodes arepositioned on the posterior thorax, so that they stimulate the nerveroots supplying muscles of expiration. It will be appreciated that acurrent may be delivered via one or more of the electrodes and returnedvia different electrode(s). Furthermore, not all of the electrodes maybe “active”during any given breathing cycle. For example, it may bedesirable to alternate between stimulating primarily two or moredifferent muscles or groups of muscles in alternate breathing cycles orin successive breathing cycles during which a stimulus is delivered.

The characteristics of the electrical stimulus (also referred to hereinas “stimulus parameters”) can be selected by one of skill in the art tocause contraction of at least some expiratory muscle(s) without causinguntoward effects such as unacceptable discomfort or heat.Characteristics of the stimulus that may be selected include, e.g.,frequency, amplitude, duty cycle, pulse shape, pulse width, pulseduration, etc. In some embodiments, a stimulus delivered in synchronywith exhaling comprises a pulse train delivered at between 1 Hz and 200Hz, with an amplitude of stimulation between 30 mA and 500 mA, and apulse width between 10 μs and 100 μs, for a duration between 0.1 secondsand 2 seconds. In some embodiments, a voltage is between 0.1 V and 5 V.It will be understood that a variety of suitable combinations ofparameters can be selected within the foregoing ranges or outside theseranges. In some embodiments a pulse width of between 100 μs and 1,000 μsmay be used. In some embodiments, a voltage between 5 V and 300 V may beused. In some embodiments, a voltage between 50 and 200 V, e.g., about100-150 V, may be used. In some embodiments, a voltage up toapproximately 300 V and/or currents up to around 100 mA may be used witha stimulation period of about, e.g., 0.1 to 0.5 ms. In some embodiments,high voltage stimulation voltages up to 1000 V and/or currents up toover 1000 mA may be used, e.g., with a very brief stimulus duration. Ifthe stimuli are delivered externally, stimulus parameters may beselected based at least in part on the different depth within the bodyto which the stimulus is to be delivered.

In some embodiments, a stimulus delivered in synchrony with anexhalation consists of a single pulse. In some embodiments, theamplitude of the pulse or pulses varies within the exhalation. Forexample, the pulse(s) may be triangular, square, rectangular,sinusoidal, partial sinusoidal, sawtooth, etc. In some embodiments inwhich multiple pulses are delivered within an exhalation period, thepulse width can vary. Variation of pulse magnitude and/or width can belinear. For example, a pulse train may begin at a 25 μs pulse width andincrease in a linear manner to a pulse width of about 300-400 μs over a1 second period of stimulation at, e.g., 50 Hz. Non-limiting examples ofstimulus parameters are: (1) 1-second pulse train at 45 Hz, amplitude ofstimulation 60-100 mA, and pulse width 25 μs; (2) single pulse,amplitude of stimulation between 50 mA and 450 mA, pulse width 200 μs.In some embodiments, the stimulus parameters are selected to causegradual rather than abrupt contraction of the muscle(s), e.g., by usinga varying (increasing) pulse width and/or amplitude within a stimulusperiod.

In some embodiments, stimuli having different characteristics may bedelivered to different muscles using different electrodes. Furthermore,different stimuli may be delivered to different portions of a muscle.For example, stimulus parameters appropriate to stimulate and causecontraction of the upper portion of the abdominis rectus, lower portionof the abdominis rectus, transversus abdominis, and/or obliques may beselected, and corresponding stimulus may be delivered specifically tothose regions (e.g., via overlying cutaneous electrodes). Electrodesizes and shapes may be selected from a variety of alternatives so as tooptimize stimulation and cause contraction of particular muscle(s) orportions thereof and/or to avoid or minimize stimulation and contractionof other muscle(s) or portions thereof. (It is noted that “optimize”,“optimal”, and like terms as used herein do not require an absoluteoptimum or “best” among all possible alternatives but rather generallyrepresent one or more preferred alternative(s) (e.g., for a particularpurpose) among a variety of available alternatives. Such preferredalternative(s) may include the “best” alternative for a particularpurpose.)

The timing of delivery of the stimulus within the expiratory phase ofbreathing can vary. In some embodiments, delivery of the stimulus istriggered by the end of inspiration. In some embodiments delivery of thestimulus is triggered by the onset of exhalation (e.g., by the beginningof a decrease in lung volume). A change in magnitude or slope or rate ofchange of slope of a quantity detected by a sensor (or a derivedquantity such as tidal volume) can be used to detect, e.g., the onset ofexhalation and/or the end of inspiration. In some embodiments, a peakdetection or zero crossing detection algorithm may be used for one ormore such purposes. As noted above, the delivery of the stimulus canstart at a predetermined time after the end of inspiration or apredetermined time after the onset of exhalation. For example, deliverycan begin between 0.5 sec and 2 sec after the onset of exhalation andlast for an appropriate amount of time to cause contraction of musclesof exhalation but allow sufficient time for such muscles to at least inpart cease contracting before inspiration begins. In some embodiments astimulus lasts for between 1 and 1.5 seconds. In some embodiments, thestimulus delivery is timed so as to increase the force of contraction ofexpiratory muscles during the latter 0.5-1 seconds of exhalation. Insome embodiments, a signal is provided to the stimulus device based onanalyzing the subject's breathing, so as to terminate the stimulus inadvance of or at the beginning of inspiration. Thus in some embodiments,at least two signals are provided to the stimulus device (within arespiratory cycle), wherein a first signal causes delivery of thestimulus and a second signal terminates delivery of the stimulus withinthat respiratory cycle. It will be understood that a second signal maybe a change in one or more characteristics of a first signal. Forexample, a first signal may comprise a waveform. An alteration in theamplitude and/or frequency of the waveform may serve as a second signal.Different amplitudes and/or frequencies may encode multiple distinctinstructions to the stimulus device.

A set of stimulus parameters or a sequence of different sets of stimulusparameters may be referred to as a “program” or “protocol”. Differentstimulus protocols may be selected, e.g., to increase force production,take account of different activity levels, and/or, in some embodimentsof the invention, to increase muscle strength or endurance, enhancefatigue resistance, etc. In some embodiments, a protocol includesgradually changing at least some of the stimulus parameters over time.For example, the stimulus may begin at a low intensity or frequencyduring a given session and increase in intensity or frequency over,e.g., a predetermined time period (which may in some embodiments beselected by a user) or based at least in part on assessment ofrespiratory or other parameters of the subject by the apparatus itself.

As described herein, in some aspects, the invention relates to usingfeedback from a respiratory sensor to deliver a stimulus to the lowerthorax and/or the abdomen of a subject when the subject is exhaling,e.g., so as to assist the subject with exhaling. In some embodiments ofthe invention, at least some stimulus parameter(s) may be adjusteddynamically (e.g., on a breath-to-breath basis or over an average of anumber of breaths) based on input from one or more sensor(s). Forexample, the timing (e.g., relative to the end of inspiration or onsetof exhalation), duration, intensity, frequency, and/or location of thestimulus can be adjusted. In some embodiments, such adjustment is basedat least in part on the tidal volume inhaled prior to a particularexhalation during which the stimulus is delivered. In some embodiments,the apparatus analyzes the effect of a stimulus on the subject'sbreathing and adjusts the stimulus. The invention may thus employfeedback to adjust, e.g., optimize the stimulus parameters.

The stimulus can be generated, for example, using any of a wide varietyof available stimulus generators or modifications thereof. In someembodiments a constant current stimulator is used. In some embodiments aconstant voltage stimulator is used.

In some embodiments, a commercially available abdominal musclestimulator is used, and/or stimulus parameters employed in such deviceare used; however in some embodiments, delivery of the stimulus islimited to the expiratory phase of breathing. The stimulus device may bean electrical abdominal muscle stimulator which, in some embodiments, isin the form of a belt (and may be referred to as an abdominal toningbelt). Exemplary devices that may be used to stimulate one or moreabdominal muscles are described, e.g., in U.S. Pat. Nos. 4,763,660;6,341,237; U.S. Pub. Nos. 20040039426; PCT application publicationsWO/2000/041764; WO/2006/121463; WO/2006/113802; WO/2010/136486, andreferences therein. Abdominal muscle stimulators are commerciallyavailable, e.g., the devices known as “Flex Belt” or “Slendertone FlexGoAbdominal Toning System”. A number of these devices have been cleared bythe U.S. Food & Drug Administration (FDA) for muscle conditioningpurposes. See, e.g., FDA 510(k) devices under Product Code ngx. BeurerGmbH (Ulm, Germany) offers abdominal muscle stimulation belts such asmodels EM30 and EM35 abdominal toning belts.

In some aspects, the inventive apparatus comprises a RIP sensor orpiezoelectric respiratory sensor in signal communication with anabdominal muscle stimulator. In some embodiments, the sensor andabdominal muscle stimulator are directly connected via a conductive wireor cable. In some embodiments, the sensor and the abdominal musclestimulator are both connected to a component that accepts an inputsignal from the sensor and delivers an output signal to the abdominalmuscle stimulator, wherein the output signal causes the abdominal musclestimulator to stimulate at least some abdominal muscles, e.g., at leastthe rectus abdominis. The component can comprise appropriate electronicsto analyze the signal received from the sensor, determine whenexhalation is occurring, select appropriate stimulus parameters, and/ordeliver an appropriately timed signal to the abdominal muscle stimulatorso that the abdominal muscle stimulator will stimulate the abdominalmuscles during exhalation.

In some embodiments magnetic stimulation of the expiratory muscles isused, optionally together with electrical stimulation. For example, thespinal nerve roots around the level of T8-T12 may be activated, e.g., bydelivering stimulation, e.g., magnetic stimulation over the T10 spinousprocess. A stimulus may also or alternately be delivered to otherlocations on the posterior thorax in certain embodiments of theinvention.

In some embodiments of the invention, the device is at least in partimplanted, e.g., into the subject's thorax or abdomen, and the electricand/or magnetic impulses are delivered internally, e.g., to efferentnerve(s) supplying expiratory muscles and/or to the muscles themselves.

In some embodiments, a subject's breathing pattern is analyzed (e.g.,using a spirometer) and/or one or more physical or neuromuscularcharacteristics such as chest and/or abdominal dimension(s), expiratoryand/or inspiratory muscle strength, sensitivity of efferent and/orafferent nerve(s) supplying said muscle(s) is/are assessed, e.g., priorto using the apparatus. The analysis may be used, e.g., to calibrate orselect the sensor(s) and/or stimulus device based at least in part onthe subject's individual breathing pattern and/or physicalcharacteristics. Appropriate parameters or ranges of parameters for thestimulus, electrode number and/or position, etc., may be selected(either automatically by the apparatus itself or by a health careprovider or other appropriately trained individual) to provide effectiveand well tolerated stimulation. For example, the minimum electricalstimulus required to reliably elicit effective contraction of one ormore expiratory muscle(s) (e.g., the rectus abdominis) or to achieve adesired level of reduction in EELV and/or the maximum stimulus that maybe delivered without causing undue discomfort may be determined In someembodiments stimulus parameters that are the minimum required (e.g.,minimum current required) to produce observable contraction (e.g.,observable to the naked eye) of a selected muscle or muscles of aparticular subject are used. In some embodiments stimulus parameters atthe maximum level (e.g., maximum current) that the subject canreasonably tolerate arc used. In some embodiments stimulus parametersbetween the afore-mentioned minimum and maximum are used. Thus in someaspects, the invention provides breathing assistance apparatus that iscustomizable based on a subject's individual characteristics.

In some embodiments the apparatus is capable of detecting differentbreathing patterns, e.g., breathing patterns associated with cough,quiet breathing, breathing patterns associated with speaking, etc. Insome embodiments, the apparatus adjusts one or more stimulationparameters and/or signal conditioning procedures based at least in parton detection of different breathing patterns. For example, stimulusintensity and/or duration may be altered based at least in part on thebreathing pattern. In some embodiments stimulation is stopped duringcertain breathing types, e.g., breathing types associated with speaking,and, in at least some embodiments, stimulation is restartedautomatically after a subject stops speaking. In some embodiments,detection of different breathing patterns is performed using astatistical classifier such as a maximum likelihood classifier or aBayesian classifier. In some embodiments, detection of differentbreathing patterns is performed using thresholds, e.g., using theminimum amplitude of the sensor signal during inhalation to distinguishbetween cough and quiet breathing. In some embodiments, a set ofbreathing pattern “training examples” of different breathing types isacquired for a particular subject and used to generate a model orreference pattern that can be used to subsequently assign breathingpatterns into one category or another. In some embodiments a model orreference pattern is generated for a subject in various positions, e.g.,lying down, sitting, standing, walking. In some embodiments an algorithmbased on a cross-correlation analysis of a subject's breathing patternwith one or more reference patterns for various breathing types in thatsubject may be used. See Gollee, H., et al., Med Eng Phys. 29(7):799-807(2007) and/or Gollee, H. et al., Technol Health Care. 16(4):273-81(2008) for an example of detecting and distinguishing breathing patternsassociated with cough and quiet breathing using cross-correlation. Anyof various machine learning approaches known in the art may be used invarious embodiments. In some embodiments an apparatus comprises orinterfaces with an accessory sensor or device that detects subjectmovement that is not part of the breathing cycle, such as walking orvoluntary movements during sleep such as turning over. Such sensor ordevice may comprise an accelerometer or may comprise an electrode placedon an arm or leg, for example. In some embodiments input from anaccessory sensor or device is used to determine the nature or intensityof the subject's physical activity, and, in some embodiments, suchinformation is used to adjust one or more stimulus parameters or signalconditioning parameters. For example, in some embodiments informationregarding a subject's movement is used to determine whether input from abreathing sensor contains an artifact arising from movement that is notpart of the breathing cycle.

It is also within the scope of the invention to deliver a blockingstimulus that blocks contraction of one or more muscle(s) and/or blocksconduction by one or more nerve(s). For example, it may be desirable toblock sensory impulses during at least part of a respiratory cycle. Thetime period within a respiratory cycle during which the blockingstimulus is delivered may or may not overlap with the time period inwhich the stimulus that elicits contraction is delivered. In someembodiments, contraction of at least some of the lower externalintercostal muscles (located in intercostal spaces 7 and below) isblocked while contraction of at least some of the lower internalintercostal muscles (located in intercostal spaces 7 and below) isstimulated. Appropriate parameters for blocking rather than elicitingcontraction may be selected. Different sets of electrodes may be usedfor the different stimuli.

One, two, or more pulse generators and/or current or voltage sources maybe provided, e.g., to permit convenient delivery of multiple stimuli.

In some embodiments of the invention, at least some muscles ofinspiration are stimulated (electrically or magnetically) while asubject is inhaling. In other embodiments, such stimulus is not provided(or any such stimulus is insufficient to cause contraction orsignificant change in force generated by such muscles). For example, thediaphragm is not stimulated and/or the external intercostal muscles arenot stimulated (or any such stimulus is insufficient to causecontraction or significant change in force generated by such muscles).In at least some embodiments of the invention, a stimulus is notdelivered to the central nervous system. In at least some embodiments ofthe invention, a stimulus is not delivered to the phrenic nerve.

Electrodes

A variety of electrodes and electrode attachment means can be used inthe apparatus of the invention, e.g., for sensing and/or for delivery ofan electric stimulus. For example, electrodes may be contained in padsthat adhere to the skin. Electrodes may be disposable (intended for onlyone to several uses) or may be intended for medium term use (e.g.,between 1 week and 6 months) or long term use (e.g., 6 months or more).Electrodes suitable for contacting the human body externally (on theskin) or internally are known in the art. An electrode may be a “wet”electrode that requires use of a contact gel when used on the skin or a“dry” electrode that does not require a contact gel. In someembodiments, an electrode is made at least in part of a conductingcarbon material. In some embodiments, a conducting polymer is used. Forexample, a conducting polymer based on 3,4-ethylenedioxythiophene suchas PEDOT (poly(3,4-ethylenedioxythiophene)) or a PEDOT:PSS(poly(3,4-ethylenedioxythiophene)) poly(styrenesulfonate) composite maybe used to fabricate a dry electrode. An electrode suitable forplacement on the skin can be incorporated into an adhesive patch or pador attached to a garment (e.g., by sewing, snap or button fasteners,Velcro, or other fastening means). Electrodes can be independentlypositionable. In some embodiments, electrodes are connected to oneanother or provided as an electrode array, e.g., arranged in apredetermined pattern with respect to one another.

Axelgard Manufacturing Co., Ltd. (Falbrook, Calif.) and PCP Medical,Inc. (Batavia, N.Y.) supply a range of different electrodes that may beused in various embodiments of the invention. For example, PALS®,UltraStim®, or ValuTrode® electrodes (Axelrod Manufacturing Co., Ltd.)may be used in various embodiments of the invention.

Mechanical Stimulus Device

A device that delivers a mechanical stimulus to the lower anteriorthorax and/or abdomen may be implemented in a variety of ways. Themechanical stimulus typically delivers sufficient force to the subject'slower anterior thorax and/or abdomen to cause an increase inintrathoracic pressure, which assists in exhalation. For example, theexternal compression may be sufficient to push the abdominal contentsup, facilitating expiration. As the external compression is relaxed,abdominal contents return to their uncompressed position, e.g., by meansof gravity and/or elastic recoil, permitting inspiration to occur.

In some embodiments, a mechanical stimulus device comprises anelectroactive polymer (EAP). Electroactive polymers are polymers thatexhibit a change in size or shape when stimulated by an electric field.Examples of such polymers are described, e.g., in U.S. Pat. Nos.6,249,076; 6,545,384; and 6,376,971. See also U.S. Pat. No. 7,491,185for discussion. EAPs can comprise conductive polymers, ionicpolymer-metal composites (IPMCs), or responsive gels. Polyaniline,polypyrrole, polysulfone, and polyacetylene are exemplary EAPs whose useis contemplated (optionally combinations thereof may be used). EAPs maybe in the form of fibers, which can be woven directly into a garment orbelt. The fibers may be interspersed in a garment or belt such that theyextend circumferentially around the subject's lower anterior thoraxand/or abdomen in one or more substantially horizontal strips or rows,which may be separated by regions that do not comprise the EAP.

In some embodiments, a mechanical stimulus comprises pneumaticallydriven compression. For example, the device can comprise one or morecompartment(s) or bladder(s) into which a gas (e.g., air) can beintroduced or released. One or more compartment(s) is/are positionedsuch that expansion of the compartment(s) by introduction of a gascompresses the anterior thorax and/or lower abdomen. In someembodiments, a gas is moved back and forth between two compartments.During exhalation, gas is introduced into a compartment positioned abovethe lower anterior thorax and/or abdomen, thereby compressing theseregions. The gas is released (e.g., into the other compartment) prior toor shortly after the onset of inhalation. The compartment(s) may besecured to the subject's body using a harness, yoke, or corset assemblyor the like. Use of pneumatic artificial muscles that at least in partencircle a subject's lower thorax and/or abdomen are also envisioned.Compressed gas or a compressor may be provided.

In other embodiments, mechanical force is provided by motorized beltspositioned around the subject's chest and/or abdomen that tighten duringexhalation and then loosen.

Parameters for the mechanical stimulus may be selected to provide asteady or gradually increasing compressive force and may avoiddelivering a sudden impact to the thorax or abdomen or an unduly rapidand potentially uncomfortable change in compressive force experienced bythe subject. The mechanical stimulus may last, for example, for betweenabout 0.5 and 3 seconds in various embodiments.

Power Supply

The apparatus of the invention can comprise a power supply that supplieselectric energy to the stimulus generator. Energy may be obtained from asuitable energy source such as an electrical energy transmission systemsupplying AC voltage or energy storage device such as one or morebatteries. A power supply may be implemented as a discrete, stand-alonedevice or as an integral component of the device. A power supply cancomprise one or more batteries, which can be provided as a battery pack.The batteries can be rechargeable. The apparatus can comprise a powercord that can be plugged into a standard electrical outlet, e.g., foruse while the subject is not ambulating or remains close to the outletand/to permit recharging the batteries. In some embodiments, a batterypack (or power supply) is separable from the remainder of the apparatusto permit conveniently charge one battery or set of batteries whileusing the other(s). A power supply can comprise a safety feature such asa current or voltage limiting circuit.

Controller

In some aspects, the apparatus comprises a controller that serves as alink between one or more sensor(s) and a stimulus device. The controllermay comprise a processor (e.g., a microprocessor), memory (e.g., bothROM and RAM), means for accepting one or more input(s) (e.g., from oneor more sensor(s)), and means for providing one or more output(s) (e.g.,to stimulus device). In some embodiments, a microcontroller is used, inwhich the afore-mentioned functions are provided by a chip comprising asingle integrated circuit and multiple pins for input/output. Thecontroller may analyze signal(s) received from one or more sensor(s) anddetermine whether and when to provide an output to a stimulus device.For example, the controller receives signal(s) from one or moresensor(s), analyzes the signal(s), and outputs a signal to a stimulatorin response to said signal(s). The stimulator then delivers a stimulusto the subject in response to the signal from the controller.Optionally, the controller selects stimulus parameters based at least inpart on analysis of the signal(s) received from the sensor(s). Theanalysis may consider signal(s) received during multiple breathingcycles. For example, if the breathing rate is increasing over time orexceeds a predetermined value, or if the duration of exhalation isdecreasing over time, the controller may change one or more parametersof the delivered stimulus to increase so as to result in more intensemuscle contraction. In some embodiments a controller may alter one ormore stimulation parameters for a given breath type, e.g., quietbreathing, based on sensor feedback, e.g., to account for minorvariations. For example, in some embodiments increasing intensity ofstimulation is provided if the amplitude of a breath signal decreasesover time, e.g., over at least a specified number of breath cycles.

It will be appreciated that signal processing and analysis functionalitymay be provided at least in part by the sensor(s) themselves and/or bythe stimulus device. For example, a sensor can comprise an analog todigital converter and/or be designed to provide a signal to thecontroller (or to the stimulus device) only when the physical quantitymeasured by the sensor exceeds a predetermined value.

Computer-readable instructions stored on a computer-readable medium forcarrying out at least part of the signal analysis, stimulus parameterselection functions, and/or other function(s) of the apparatus are anaspect of the invention. Computer-readable instructions may be embodiedin any tangible medium (e.g., a non-transitory storage medium) and/ormay utilize any computer programming language in various embodiments. Acomputer-readable medium may be, for example but not limited to, anelectronic, magnetic, optical, electromagnetic, infrared, orsemiconductor system, apparatus, device. Examples of a computer-readablemedium include the following:, a hard disk, a random access memory(RAM), a read-only memory (ROM), an erasable programmable read-onlymemory (e.g., EPROM or Flash memory), a portable compact disc read-onlymemory (CDROM), a floppy disk, an optical storage device, or a magneticstorage device. A computer-readable medium may in some embodiments bepaper or another suitable medium on which the program is printed orembodied, as the program can be electronically captured, for instance,via optical scanning of the paper or other medium (optionally employingoptical character recognition), then compiled, interpreted, or otherwiseprocessed in a suitable manner, if necessary, and then stored in acomputer memory and/or executed by a computer processor. In the contextof this document, a computer-readable medium may be any medium that cancontain, store, communicate, propagate, or transport data orcomputer-executable instructions.

Garment or Belt

In some embodiments, at least one component of the inventive apparatusis integrated into a garment, by which is meant that the component isattached to the garment as an integral part of the garment. For example,the sensor, electrode(s), stimulus device, and/or electrical cordsconnecting two or more component(s) are integrated into a garment. Insome embodiments, the sensor, stimulus device, or both (or one or morecomponent(s) thereof) are attached to a garment but are readilydetachable, e.g., they are attached by a fastening means selected topermit easy detachment.

A garment may be an upper body garment that a subject can pull over thehead and thorax. It is typically a close-fitting garment that may fitsnugly around the thorax and, in some embodiments, extends to and fitsaround at least part of the abdomen (e.g., the upper abdomen). In oneaspect, the invention provides a comfortable and unobtrusive garmenthaving at least one sensor integrated therein, wherein the sensor isoperably connected to a device adapted to deliver a stimulus to asubject, wherein the stimulus is effective to assist the subject withbreathing. The garment may be an undergarment suitable for wearing undera conventional shirt or blouse (if desired). For example, the garmentmay be a vest or “T-shirt”. In some embodiments, the garment issleeveless while in other embodiments sleeves (either short or longsleeves) are provided. In other embodiments, at least the device fordelivering the stimulus may be incorporated into a lower body garmentthat a subject pulls on over the legs, e.g., an undergarment such as apair of briefs or a girdle, or a pair of shorts, tights, pants,leggings, etc. The lower body garment fits at least around the subject'sabdomen and, optionally, at least part of the lower thorax. In someembodiments the garment is a bodysuit or leotard-like garment.

In some embodiments, the sensor, stimulus delivery device, or both, areintegrated into a belt that is worn around the waist (i.e., the part ofthe abdomen between the rib cage and hips). The belt may be wider than aconventional belt used as a clothing accessory and may in someembodiments encompass at least a portion of the lower rib cage and/orextend down over at least part of the hip region. The belt is typicallycomprised of a flexible material such that it can encircle the subject'swaist. It will typically have a fastening means such as one or morebuckles, hooks, snaps, buttons, or Velcro fasteners. The belt may beflexibly adjustable about the abdomen.

The sensor and the stimulus device may be integrated into the samegarment or belt, or each may be integrated into a different garment orbelt. In some embodiments, the stimulus device is integrated into a beltwearable around the subject's waist while the sensor device isintegrated into an upper body garment. The sensor and device maycommunicate via a direct electrical connection or wirelessly. In someembodiments, a belt or garment comprises multiple sites for potentialattachement of electrodes, thereby permitting an individual (e.g., thesubject or a health care provider or other caregiver) to adjust thenumber and/or position(s) of the electrodes (for sensing and/or stimulusdelivery).

The garment or belt may be made at least in part of a stretchablematerial comprising fibers with high elasticity such as Spandex (alsocalled Lycra or elastane), Darlexx, or polyurethane, to facilitate snugfitting, which fibers may be intermixed with other fibers such as cottonor polyester. The garment or belt may be composed at least in part of awoven, non-woven, or meshlike fabric or textile. In some embodiments, agarment or belt is comprised at least in part of an elastomeric materialsuch as a synthetic rubber material, e.g., polychloroprene (Neoprene).The garment or belt may have a Spandex or nylon-containing backinglining at least on one side for contacting the skin, e.g., to improvecomfort. In some embodiments, the garment or belt comprises multiplepanels or sections, wherein at least some of the panels or sectionscomprise a stretchable material. The garment or belt may comprisepadding or cushions or the like or may in part be composed of a soft andcushiony material that may serve to protect sensitive component(s)and/or improve the comfort of the subject.

Conductive strips may be woven into or attached to the garment or belt,e.g., as sensors and/or to transmit signals from sensor(s) and/or to orfrom a stimulus device. Components such as a sensor or electrode(s) maybe attached to the garment or belt by, e.g., sewing, embroidering,embedding, adhering (e.g., using a suitable adhesive that, in someembodiments, is pressure-sensitive), weaving, enclosing at least part ofthe component between portions or layers of fabric, lacing, use of tabs,slots, or grooves, tapes, zippers, etc. In some embodiments, a sensorand/or electrode is printed or stamped onto a fabric. The garment orbelt may be washable. In some embodiments, the garment or belt isdesigned so that sensor(s) and/or electrode(s) for delivering a stimuluscan be positioned at a variety of different locations. For example, thegarment or belt may comprise multiple snap fastener disks or press studdisks that would permit attachment of a sensor or electrode thereto.

As noted above, electroconductive or piezoelectric fibers can be used assensors in various embodiments of the invention. Such fibers mayoptionally be an integral part of a garment or belt. For example, thegarment or belt may comprise one or more regions, optionally in the formof strips or bands, that comprise conductive or piezoelectric fibers orfabric portions. Such regions may optionally extend around the subject'schest or abdomen. They may be substantially straight or arranged in azig-zag, sinusoidal, or similar-shaped pattern.

A garment or belt may contain one or more “channels” or “tunnels”comprised of two or more fabric layers through which one or moreelectric cords or cables can be “threaded” to connect various componentsof the apparatus. A garment or belt may comprise one or more “pockets”or spaces between two or more fabric layers into which one or morecomponents of the apparatus may be placed. For example, a power supply,controller, compression compartment, electric impulse generator, etc.,may be placed in a pocket or between fabric layers. Pockets may beconnected by channels or tunnels within the garment or belt.

In particular embodiments, the invention provides a wearable abdominalmuscle stimulating belt comprising a sensor capable of sensing when asubject is exhaling. In some embodiments, the belt comprises two or moresensor(s). The sensors may be positioned so that a first sensor contactsthe right upper quadrant of the anterior abdomen and a second sensorcontact the left upper quadrant of the anterior abdomen. The sensor(s)may detect strain and/or abdominal movement that accompanies breathingactivity. The sensor(s) may be positioned on the belt in a preferredorientation for sensitivity and/or specificity of sensing when a subjectis exhaling. In some embodiments, the sensor(s) are piezoelectricsensors.

It is particularly contemplated to attach or incorporate any one or moresensor(s) or sensor types mentioned herein or other suitable sensor(s)into an abdominal muscle stimulating belt. It is also particularlycontemplated to provide an abdominal muscle stimulating belt comprisingmeans for attaching attach or incorporating any one or more suchsensor(s). It is also particularly contemplated to use the abdominalmuscle stimulating belt with sensor(s) to stimulate at least oneabdominal muscle in phase with a subject's exhalation. It isparticularly contemplated to provide an apparatus comprising anabdominal muscle stimulating belt with sensor(s) and control means toprocess signal(s) from the one or more sensor(s) and cause the deliveryof an electrical stimulus to one or more abdominal muscle(s) when asubject is exhaling.

In some embodiments, the belt is equipped with means that permitattachment of one or more sensor(s) thereto, such that the sensorscontact the subject in a manner appropriate to permit the sensor(s) todetect when a subject is exhaling. In some embodiments, the beltcomprises one or more loops (similar to belt loops found on garmentssuch as trousers), wherein the loops are located on the surface of thebelt that would contact the subject's skin when the belt is in use. Insome embodiments, the sensor(s) are in the form of bands or strips thatcan be attached to the belt by sliding them through the loops of thebelt. In some embodiments a sensor comprises a tab (e.g., a short stripof material attached to or projecting from a side of the sensor), whichcan fit into a slot or slit in the belt. The tab may be made at least inpart of a reasonably stiff material, e.g., a plastic material. The innersurface of the belt may alternately comprise, or further comprise, oneor more hooks, loops, eyes, snaps, slots, slits, grooves, or other meansor features that would permit secure fastening of the sensors. Thus theinvention encompasses use of attachment systems wherein a stimulusdevice, e.g., an abdominal muscle stimulating belt, comprises a firstelement of the attachment system and a sensor comprises a second elementof the attachment system, wherein the first and second elements arecompatible with each other so that the sensor may be securely attachedto the belt. Example of such attachment systems and the respectiveelements include, e.g., “male”and “female” portions of a snap; tab andslit/slot; hook and loop; hook and hook; hook and eye; button and buttonhole. (It is noted that hook and loop, is intended to encompass use ofminiature hooks, loops, and/or eyes, e.g., as in Velcro). One or moresuch attachment systems may be used. A first element may be provided bythe belt and a second element provided by the sensor, or vice versa.

In some embodiments, the sensor(s) constitute an integral part of thebelt. For example, one or more sensor(s) may be sewn or securely adheredto the side of the belt that would contact the subject when in use.

The locations of the integral sensor(s), attachment element(s), and/orelectrodes may be selected so that the sensing element(s) do notspatially overlap with the electrodes. In some embodiments, sensingelements and electrodes are spaced apart along the inner side of thebelt or garment.

Kits

The components of the inventive apparatus can be provided separately ortogether e.g., within a single package or “kit”, within which they maybe individually wrapped or otherwise separated. The kit or package wouldcontain at least a sensor (and optionally associated elements such asbands to secure the sensor)and a stimulus device (e.g., an abdominalmuscle stimulator), and optionally further include one or more of thefollowing: electrode(s), electrode gel, controller, power supply, wiresfor connecting component(s), instructions for use of the apparatus, etc.In some embodiments, a kit or package comprises an abdominal musclestimulator (e.g., in the form of a belt) and a RIP sensor orpiezoelectric sensor suitable for sensing breathing. In someembodiments, the sensor is incorporated into a garment or belt.Optionally the kit or package contains a notice (e.g., label or packageinsert) indicating that the apparatus has been cleared or certified by aregulatory authority such as the FDA, e.g., for over the counter and/orprescription use. In some embodiments one or more indications for whichthe apparatus is approved is mentioned in the notice. For example, insome embodiments a notice indicates that the apparatus is approved foruse to assist breathing, reduce hyperinflation, and/or improve exercisetolerance in a subject suffering from obstructive respiratory disease,e.g., COPD. In some embodiments a notice indicates that the apparatus isapproved for use in assisting with ventilator weaning.

Features and Uses

Without limiting the invention in any way, this section provides furtherinformation relating at least in part to various features and uses ofembodiments of the inventive apparatus and methods. In some aspects, aninventive apparatus is used to treat a subject. A subject is typically ahuman although it is envisioned that a subject may, for therapeuticand/or testing purposes, be a non-human animal, e.g., a non-humanprimate or domesticated animal, e.g., companion animal such as a dog orcat. In some embodiments the subject is male. In some embodiments thesubject is female. In some embodiments the subject is an adult, c.g., ahuman at least 18 years of age, e.g., between 18 and 100 years of age.Many subjects with COPD may be adults over the age of 40. An effectivetreatment in some embodiments of the invention reduces the severity ofone or more symptoms, signs, or manifestations of a disease, disorder orcondition during at least part of the time that the treatment is beingused by the subject.

A subject suffering from a respiratory disorder, e.g., an obstructiverespiratory disorder such as COPD, can be diagnosed as known in the art.See, e.g., the GOLD Report. The increase in airway resistance is evidentby a decrease in the forced expiratory volume in 1 second (FEV₁), e.g.,as measured by spirometry or a peak flow meter. COPD may be defined as aforced expiratory volume in 1 second to forced vital capacity ratio(FEV₁/FVC) that is less than 0.7. In some embodiments, a subject hasCOPD of Stage II, III, or IV as defined in the GOLD Report based onpost-bronchodilator assessment of FEV₁/FVC and FEV₁. For example, asubject may have FEV₁/FVC<0.70 and 30%≤FEV1<50% of predicted value(e.g., <50% of value predicted for a healthy individual based onindividuals's age, sex, and height) or FEV₁/FVC<0.70 and FEV₁<30% ofpredicted. In some embodiments, a subject has symptoms of COPD not fullyreversible with bronchodilator therapy and an FEV₁/FVC in the lower 5%of healthy individuals in the subject's age group. Otherspirometry-based definitions of airway obstruction (e.g., BritishThoracic Society definition) could be used. In some embodiments asubject exhibits EFL as assessed, e.g., using the NEP technique. Forexample, in some embodiments a subject has a score of 1 or 2 using a 3point scale, or a score of 0 to 4 using 5 point scale, or EFL less than50% expiration using the continuous scale.

In some aspects, use of an inventive breathing assistance apparatusreduces the objective or subjective effort required for the subject(e.g., a subject with an obstructive respiratory condition, e.g., COPD)to at exhale and/or inhale, e.g., if the subject feels that it isgenerally easier to exhale and/or inhale when using the apparatus thanwhen not using the apparatus (at the same activity level). As notedabove, it should be understood that any one or more benefits provided bythe inventive apparatus may not be evident immediately upon the subjectbeginning a session of using the apparatus. For example, some time maybe required for the stimulus provided by the apparatus to result inexhalation of air trapped in the subject's lungs. For example, the EELVmay gradually decrease over a period of time after the beginning of asession. In some embodiments, one or more beneficial effects provided byan inventive apparatus may be present for at least some time after theend of a session. For example, an effect may be evident for at least 15minutes after a session, e.g., between 15 and 30 minutes, or up to 1, 2,4, 6, or more hours after the end of a session. It will be appreciatedthat the effect may diminish over time during such period. Thus abeneficial effect is considered to result if the subject experiences theeffect during at least part of a session and/or if the subjectexperiences the effect after completion of the session.

In some embodiments, use of an inventive breathing assistance apparatusresults in a decrease of between 5%-75%, between 5% and 50%, or between5% and 25% in the subject's resting EELV (e.g., as compared with thesubject's resting EELV before the first use of the device by thesubject). In some embodiments, use of an inventive breathing assistancesystem results in a decrease of between 50 ml and 200 ml in thesubject's resting EELV (e.g., as compared with the subject's restingEELV before the first use of the device by the subject). In embodiments,use of an inventive apparatus results in a decrease of between 5%-75%and/or a decrease of between 50 ml and 200 ml in the subject's EELVduring or immediately after a period of exercise, e.g., walking (e.g.,as compared with the subject's EELV after such exercise before the firstuse of the device by the subject). In some embodiments, an inventiveapparatus used by a subject experiencing dynamic hyperinflation (e.g.,due to a COPD exacerbation) results in a decrease in the subject's EELVsuch that it is within 125% of that measured for the subject when notexperiencing dynamic hyperinflation or a COPD exacerbation. In someembodiments, use of an inventive apparatus results in a decrease in asubject's EELV so that it does not exceed 150% or, in some embodiments,so that it does not exceed 125% of the average predicted EELV forhealthy, matched subjects. As noted above, a change in EELV may existduring part of a session using the device and/or may continue for aperiod of time after a session is over. A “matched subject” willtypically be reasonably matched with regard to age, height (and/or otherrelevant dimension(s)), optionally sex-matched. One of skill in the artwill be aware of or can obtain suitable standard ranges for normal EELV(or other lung volumes, lung capacities, or characteristics relevant tobreathing) in subjects. Assessment of EELV (or other lung volumes, lungcapacities, or characteristics relevant to breathing) can be performedusing any of the methods mentioned herein or others known in the art.Such measurement may be averaged over multiple breaths.

Using an apparatus of the invention that stimulates the abdominalmuscle(s) may train these muscle(s) and may, for example, result in anincreased strength and/or endurance. Thus the apparatus may improve asubject's own ability to exhale independent of the direct effect of thestimulus itself. It is also contemplated that the experience of usingthe apparatus may help train a subject how to use their abdominalmuscles more effectively in exhaling. For example, the inventiveapparatus may help the subject become aware of the capacities of theirabdominal muscles and/or may help the subject gain increased controlover their contraction and/or its timing. Using an inventive apparatusmay teach a subject when to contract the abdominal muscles in order tobetter exhale. For example, an apparatus may assist the subject withappropriate timing of contraction with respect to the onset ofexhalation and/or appropriate duration of contraction in order tofacilitate one or more outcomes or goals such as, e.g., to exhale aselected volume, to retain no more than a selected volume in the lungsat end-expiration, to have a selected respiratory rate or a respiratoryrate within a selected range, or to make efficient use of respiratorymuscle effort.

In some embodiments, the inventive apparatus may be used as a tool inbiofeedback. Biofeedback generally refers to a process that enables anindividual to learn how to change physiological activity, e.g., for thepurposes of improving health and/or performance and can involve becomingaware of various physiological functions using instruments that provideinformation on the activity of those same systems, with a goal of beingable to manipulate them at will. This type of learning may occurnaturally through use of the inventive apparatus, may be facilitated bya trained biofeedback practitioner, and/or may be facilitated by acomputer-based program. The computer program may communicate with theapparatus and, for example, display waveforms associated with breathing,the time of delivery of a stimulus and/or its location or strength,comparison of breathing with and without the stimulus. Information canbe presented to the user on a display. Visual and/or auditory feedbackand/or tactile feedback (e.g., electrical or mechanical) may be providedto the subject. The computer program may be written in a suitablecomputer language and may be stored on computer-readable medium; suchcomputer-readable medium is an aspect of the invention. The inventionprovides a system comprising an apparatus of the invention and acomputer, wherein the computer is programmed to execute instructions forproviding biofeedback to a user based at least in part on input receivedfrom the apparatus and/or while a subject is using the device.

In some embodiments an apparatus is capable of operating in at least twodifferent modes, e.g., (i) a first mode in which stimulus parametersselected to stimulate contraction of one or more expiratory muscles areused during those breath cycles in which a stimulus is delivered, and(ii) a second mode in which stimuli below the level of stimulation thatwould be required to stimulate contraction of the expiratory muscle(s),under ordinary conditions of use (or in some embodiments, any effect oncontraction would be insignificant in terms of its effect on exhalation,as judged by one of ordinary skill in the art) but sufficient to be feltby the subject, are delivered during at least some breath cycles. Astimulus as described in clause (ii) of the preceding sentence may bereferred to herein as a “tactile stimulus”, and the second mode may bereferred to as a “prompting mode”. In general, a tactile stimulus issufficient to elicit an action potential in at least one sensory nerve,e.g., a sensory nerve supplying the skin, but in at least someembodiments, is not sufficient to elicit an action potential in a motornerve supplying an expiratory muscle. In some embodiments a tactilestimulus is delivered at a frequency at or below about 15 Hz. In someembodiments, when operating in the second mode, tactile stimuli aredelivered during at least 50%, 60%, 70%, 80%, 90%, 95%, or 100% ofbreath cycles in which a stimulus is delivered. In some embodimentsstimulus parameters for a tactile stimulus are selected such that thestimulus does not, under ordinary conditions of use, elicit detectableexpiratory muscle contraction of muscles that are not contracting(except as a result prompting the subject through sensory stimulation asdescribed herein, e.g., below) and/or does not elicit detectableincrease in the force or duration of contraction of muscles that arecontracting (except as a result prompting the subject through sensorystimulation as described herein, e.g., below). In some embodiments, a“detectable effect” is visually observable to the naked eye. In someembodiments, a “detectable effect” is detectable by an appropriatesensor. In some embodiments, a “detectable effect” is detectable byelectromyography (EMG). In some embodiments EMG is surface EMG. In someembodiments EMG is intramuscular EMG. In some embodiments parameters fora tactile stimulus are determined empirically for a subject. Forexample, in some embodiments stimuli at the minimum level required inorder to be felt by the subject at least 80%, 90%, 95%, or more ofattempts are selected.

In some embodiments, when in a prompting mode, sensory stimuli, e.g.,tactile stimuli, are provided to serve as a cue for the subject withregard to the timing of respiration and/or respiratory musclecontraction. For example, in some embodiments a sensory stimulus, e.g.,a tactile stimulus, provides a cue as to the appropriate beginning,duration, or end or one or more phases of respiration or expiratorymuscle contraction in order for the subject to achieve a specifiedtarget with regard to, e.g., the volume exhaled or the duration ofexhalation. In some embodiments a sensory stimulus serves as a cue toprompt the subject to initiate and/or maintain exhalation and/or toinitiate or maintain or increase expiratory muscle contraction. Forexample, a subject may be instructed to continue to breathe out and/orto continue contracting the expiratory muscles for so long as he or shecontinues to feel the stimulus. In some embodiments a target is that thesubject exhales for at least a specified period of time and/or exhalesat least a specified volume. In some embodiments a target is at least inpart predetermined prior to the beginning of a particular trainingsession. For example, in some embodiments a target is that the subjectexhales for at least a selected minimum time. In some embodiments aminimum time may be calculated on an individual basis as a percentageincrease of a subject's pre-existing exhalation time when not using theapparatus. In some embodiments a target is selected based at least inpart on a subject's recent breathing activity, as detected by theapparatus. For example, if the subject's exhalation phase and/or exhaledvolume has decreased in length over each of at least a specified numberof consecutive breathing cycles (e.g., at least 3 breathing cycles), theapparatus may prompt the subject to increase the duration of the nextexhalation.

A prompting mode can be used for any of a variety of purposes in variousembodiments. For example, in some embodiments a prompting mode is usedto help a subject, e.g., a subject with an obstructive respiratorydisorder, acquire a more effective breathing pattern. In someembodiments a prompting mode is used as an exercise aid. In someembodiments an apparatus is capable of operating in a mode in which asensory stimulus is delivered during some respiratory cycles, and astimulus of sufficient strength to elicit enhanced expiratory musclecontraction is delivered during at least some of the other respiratorycycles. In some embodiments the apparatus determines whether the subjectmet a target and, in some embodiments, selects a course of action basedat least in part on whether the subject met the target. In someembodiments the apparatus determines whether the subject's breathing istrending in an unfavorable direction and, in some embodiments, selects acourse of action based at least in part on whether the subject'sbreathing is trending in an unfavorable direction. A course of actionmay be, e.g., delivering a stimulus sufficient to elicit increasedexpiratory muscle contraction during the next exhalation if the subjectfailed to meet the target and/or if the subject's breathing is trendingin an unfavorable direction or delivering a sensory stimulus (or nostimulus) if the subject met the target. For example, a stimulus thatelicits increased expiratory muscle contraction may be delivered if thesubject fails to meet a target or if the subject's breathing is trendingin an unfavorable direction. In some embodiments an unfavorabledirection is a direction indicating that the length of the subject'sexpiratory phase is decreasing. In some embodiments an unfavorabledirection is a direction suggesting that the subject is developinghyperinflation or that hyperinflation is worsening. Any reasonable timeperiod may be selected for purposes of determining whether the subject'sbreathing is exhibiting a trend in various embodiments. For example, insome embodiments a trend is detected by analyzing a subject's breathingover between 5 and 100 breaths or over between 30 seconds and 5 minutes.

In some embodiments a sensory stimulus comprises an electrical stimulus.The strength, nature, and/or other characteristics of the sensorystimulus may be selected by and/or customized appropriately for theparticular subject. For example, an electrical stimulus that does notelicit enhanced expiratory muscle contraction but is reliably perceivedby the subject may be selected based empirically. In some embodiments asensory stimulus is provided using any one or more electrodes. In someembodiments an electrode delivers either a tactile stimulus or astimulus sufficient to stimulate contraction depending, e.g., on themode in which the apparatus is operating. In some embodiments one ormore electrodes is provided solely for purposes of delivering a tactilestimulus. In some embodiments a sensory stimulus comprises an auditorystimulus or a visual stimulus. For example, in some embodiments anapparatus comprises or interfaces with a unit capable of producing oneor more sounds or equipped with one or more lights (e.g., light emittingdiodes), etc., which serve as a sensory stimulus. In some embodiments anapparatus provides information regarding the extent to which the subjectachieved the target for a particular respiratory cycle, time interval,or session.

In some embodiments an apparatus may be capable of operating in a mannerin which it stimulates one or more abdominal muscles to contract insynchrony with inspiration during at least part of the inhalatory phase.In this case, the abdominal muscles would work against the action of thediaphragm. Without wishing to be bound by any theory, it is envisionedthat causing the abdominal muscles to work against resistance in thismanner may be more efficient, e.g., may lead to greater or more rapidimprovements in strength as compared with stimulation at random timesrelative to the timing of the respiratory cycle or relative tostimulation during exhalation. In some embodiments this type offunctionality may be provided as one of multiple modes of an apparatusfor use by individuals with compromised respiratory function who are inneed of assistance with breathing. In some embodiments this type offunctionality may be provided for use for abdominal muscle toning orstrengthening purposes, e.g., by individuals who are not in need ofassistance with breathing, e.g., individuals with normal respiratoryfunction. In some embodiments a training program or monitoring of asubject may be provided at least in part over the Internet.

In some embodiments, use of an inventive apparatus reduces the severityof at least one symptom of COPD or other respiratory disorder. As notedabove, such effect may exist during part of a session and/or maycontinue for a period of time after a session is over. Such improvementmay be assessed using a variety of instruments known in in the art. Forexample, the Modified Medical Research Council (MMRC) dyspnea scale,baseline dyspnea index (BDT), Borg dyspnea score, and/or the oxygen costdiagram (OCD) may be used. See also GOLD Report and ATC/ERS Guidelinesfor various approaches to symptom assessment. In some embodiments, useof an inventive breathing assistance apparatus improves the subject'sexercise tolerance. For example, a subject may exhibit an improvement inperformance on a 6 minute walk test (e.g., an increase in the distance asubject is able to walk in 6 minutes), shuttle walk test, and/orcardiopulmonary exercise testing. See, e.g., ATS Statement: Guidelinesfor the Six-Minute Walk Test (2002) for discussion of 6 minute walktest. In some embodiments, use of an inventive apparatus provides aclinically meaningful benefit to a subject (e.g., a subject sufferingfrom an obstructive respiratory disorder such as COPD), e.g., within thesound judgement of a health care provider, e.g., a physician, optionallya physician specialized in pulmonary medicine and/or who is experiencedin the care of subjects with obstructive respiratory disorders such asCOPD. In some embodiments a benefit is evident based on measurement ofone or more respiratory parameters or derived parameters. For example,in some embodiments Peak Expiratory Flow rate (PEF), Exhaled Volume(VE), Inhaled Volume (VI), Respiratory Rate (RR), Inhaled and ExhaledMinute Ventilation (MVI and MVE), and/or Inspiratory Capacity (IC) aremeasured over one or more time periods and compared between unassistedand apparatus-assisted breathing of a subject. In some embodiments, theratio of MVE and/or VE to MVI and VI respectively are compared betweenapparatus-assisted and unassisted breathing to evaluate changes inhyperinflation, e.g., over a selected time period following thebeginning of a session, such as 1-2 minutes, wherein an increase in MVEor VE to MVI or VI, respectively, indicates a decrease inhyperinflation. In some embodiments, IC is compared betweenapparatus-assisted and unassisted breathing to evaluate changes inhyperinflation, wherein a greater IC in a subject duringapparatus-assisted breathing indicates a decrease in hyperinflation. Itshould be understood that although COPD is of major interest herein, theinventive apparatus and methods may be used, among other things, fortreating other obstructive lung disorders, other conditions in whichhyperinflation occurs, and such methods of treatment are aspects of theinvention. In some embodiments, the subject suffers from weakness of therespiratory muscles. Such weakness may arise from a variety of causes.For example, individuals who have chronic illnesses and/or who haveexperienced a period of prolonged physical inactivity (e.g., bedrest)may experience weakness of the respiratory muscles due at least in part,e.g., to muscle wasting. Individuals suffering from congenital oracquired neurological or neuromuscular conditions such as amyotrophiclateral sclerosis (ALS) or myopathic conditions such as myotonicdystrophy may benefit from use of an inventive apparatus.

In some embodiments, a subject has been on mechanical ventilation, e.g.,during and/or after a COPD exacerbation, injury, surgery, infection(e.g., pneumonia, sepsis), temporary paralysis (e.g., paralysis from acause from which a subject would reasonably be expected to be weanedfrom a ventilator within up to 3-6 months of onset), stroke, and/or dueto hypotension, cardiovascular disease (e.g., heart attack, heartfailure), shock, altered mental state, respiratory arrest, substanceintoxication (e.g., with one or more central nervous system depressantssuch as alcohol, barbiturate, or opiate), general anesthesia, acute lunginjury (e.g., due to trauma, adult respiratory distress syndrome, smokeinhalation, chemical lung injury), epileptic seizure (e.g., statusepilepticus), coma, or any other reason. An inventive breathingassistance apparatus may serve as a bridge to help wean the subject frommechanical ventilation. In some embodiments an apparatus is used whilethe subject remains on mechanical ventilation, e.g., when it is deemedappropriate (e.g., within sound medical judgement) to attempt to weanthe patient from the ventilator. In some embodiments a subject hasexperienced difficulty being weaned from mechanical ventilation, e.g.,the subject may have had one or more failed weaning attempts orexperienced significant difficulty adjusting to weaning due to ongoingrespiratory symptoms. A subject may, for example, have failed one ormore spontaneous breathing trials, e.g., one or more spontaneousbreathing trials performed using a T-piece while the subject remainsintubated or a trial extubation (e.g., the subject may have requiredre-intubation after being extubated). In some embodiments a subject onmechanical ventilation or recently extubated (e.g., extubated up to 4weeks previously) may have been on mechanical ventilation, e.g., in anintensive care unit, for at least 1-4 weeks, e.g., 4-24 weeks. In someembodiments an apparatus may be used to provide muscle stimulation whilea subject remains intubated, but with the ventilator not providingventilatory support while the apparatus is in use, or providing onlypartial ventilatory support while the apparatus is in use. Partialventilatory support by the ventilator may comprise, e.g., pressuresupport, delivering at least a minimum number of breaths per minute(e.g., in synchrony with the subject's respiratory effort), or acombination thereof. Use of the apparatus may, for example, helpstrengthen respiratory muscles (e.g., recovery of muscle strength thatmay have been lost through disuse) and/or assist a subject in learningor re-learning effective breathing patterns. In some embodiments anapparatus is used during at least some time periods in which theventilator is providing full ventilatory support, e.g., before weaningis appropriate, in addition to or instead of at such time as weaning isappropriate. Use of the apparatus by a subject who is receiving fullventilatory support may be beneficial e.g., to reduce muscledeconditioning that would otherwise be likely to occur. The apparatus,when operating in this manner, may provide stimulation in synchrony withexhalation based at least in part on signals received from theventilator and need not sense the subject's breathing, although it maydo so.

In some embodiments an apparatus may be used to assist breathing by asubject who uses or is a candidate for non-invasive ventilatory support,e.g., ventilatory support delivered via a mask. In some embodimentsnon-invasively delivered ventilatory support comprises continuouspositive airway pressure (CPAP). In some embodiments a subject using theapparatus may have a reduced need for or reduced utilization ofnon-invasive ventilatory support, e.g., as compared with a controlsubject. As used herein, a subject may be considered to be a “candidatefor” a particular therapy if there is, within sound medical judgement,at least a reasonable likelihood that a subject would benefit from aparticular therapy, e.g., sufficient likelihood to warrant givingserious consideration to using the therapy or sufficient likelihood tojustify a trial of the therapy.

In some embodiments an apparatus may be used to assist breathing by asubject who regularly uses (e.g., at least once a week, e.g., daily) oris a candidate for supplemental oxygen. In some embodiments a subjectusing the apparatus may have a reduced need for or reduced utilizationof supplemental oxygen, e.g., as compared with a control subject.

In some embodiments, the subject does not have partial or completeparalysis of one, more, or all of the expiratory muscles. For example,the subject has not suffered a spinal cord injury (e.g., partial orcomplete spinal cord transection) or brain injury causing suchparalysis. In some embodiments the subject does not have partial orcomplete paralysis of the diaphragm. In some embodiments, partialparalysis is characterized by reduced function of affected muscles, butthere is not a total loss of function. In some embodiments the subjecthas normal phrenic nerve function. In some embodiments, the subject doesnot have paraplegia. In some embodiments, the subject does not havetetraplegia. In some embodiments, the subject does not havequadriplegia.

The inventive apparatus may be used by an individual who does not sufferfrom an obstructive respiratory disorder or who may have an early stageof the disorder which is asymptomatic, undiagnosed, and/or does notwarrant therapy. In some embodiments a subject is apparently healthy. Insome embodiments a subject has one or more diseases other than anobstructive respiratory disorder. The apparatus may, for example, beused to tone, condition, and/or strengthen abdominal muscle(s). Withoutwishing to be bound by any theory, at least some persons who wish totone, condition, and/or strengthen their abdominal muscles may findcertain embodiments of the inventive apparatus more comfortable and/orpleasant to use than an abdominal muscle stimulator that delivers astimulus without regard for whether a subject is inhaling or exhaling. Apatient with an obstructive respiratory disorder may benefit fromtoning, conditioning, and/or strengthening of expiratory muscle(s) thatmay occur as a result of using an inventive apparatus. Over time thesubject's expiratory muscle(s) may become stronger and/or more resistantto fatigue.

In some embodiments an apparatus may be used by a subject who has beenor is reasonably expected to be mainly or essentially completelyconfined to a bed or chair due, e.g., to illness or injury, for anextended period of time, e.g., a period of time sufficient to have areasonable likelihood within sound medical judgement of resulting indeconditioning (e.g., loss of tone, fitness, and/or strength) of theabdominal muscles. In some embodiments the time is at least 2 weeks,e.g., at least 2-4 weeks. Use of the apparatus may, for example, reduceor prevent muscle deconditioning. In some embodiments the subject is noton mechanical ventilation and has not recently (e.g., within thepreceding 4 weeks) been on mechanical ventilation. In some embodimentsthe subject has been on mechanical ventilation within the preceding 4weeks. In some embodiments the subject has never been on mechanicalventilation.

The invention encompasses embodiments comprising use of an inventivebreathing assistance device together with additional pharmacological ornon-pharmacological therapy for an obstructive respiratory disorder.Such additional therapy may include administration of any compound(s)used in the art or potentially useful for treating a subject sufferingfrom an obstructive respiratory disorder, e.g., COPD. In someembodiments, the use of an inventive breathing assistance apparatusallows for a reduction in the use of pharmacological therapy. Forexample, a patient may be able to avoid using, or reduce their use of,systemic corticosteroids. In some embodiments, a subject may receivetraining in how to use the apparatus. In some aspects, the trainingcomprises breathing training. In some embodiments, an inventiveapparatus is used by a subject participating in a program of pulmonaryrehabilitation. In some embodiments, an inventive apparatus is used by asubject engaged in a program of exercise training (which can includeendurance (aerobic) and/or strength training). The apparatus may be usedduring and/or between training sessions.

In some embodiments, a beneficial effect resulting from use of anapparatus described herein by a subject or group of subjects may bedemonstrated by comparison with a control subject or control group ofsubjects. In some embodiments a control subject is an appropriatelymatched subject who has not used and/or does not use the apparatus. Oneof ordinary skill in the art would be able to select an appropriatematched control subject. In some embodiments a matched subject ismatched with regard to indication for use of the apparatus (e.g., COPD,ventilator weaning, etc.). In some embodiments a matched subject is alsomatched with regard to severity of the condition, and, optionally, withregard to one or more demographic variables such as age, sex, etc. Insome embodiments a historical control subject or group of subjects isused. In some embodiments a subject serves as his or her own control.For example, in some embodiments the subject's condition during use ofthe apparatus is compared with the subject's condition when not usingthe apparatus and/or the subject's condition after having used theapparatus regularly for a period of weeks or months is compared with thesubject's condition as it existed prior to starting to use theapparatus. In some embodiments a beneficial effect resulting from use ofan apparatus described herein may be demonstrated in a clinical trial.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. The scope of the presentinvention is not intended to be limited to the above Description, butrather is as set forth in the appended claims. In the claims articlessuch as “a”, “an” and “the” may mean one or more than one unlessindicated to the contrary or otherwise evident from the context. Claimsor descriptions that include “or” between one or more members of a groupare considered satisfied if one, more than one, or all of the groupmembers are present in, employed in, or otherwise relevant to a givenproduct or process unless indicated to the contrary or otherwise evidentfrom the context. The invention includes embodiments in which exactlyone member of the group is present in, employed in, or otherwiserelevant to a given product or process. It is to be understood that theinvention encompasses all variations, combinations, and permutations inwhich one or more limitations, elements, clauses, descriptive terms,etc., from one or more of the listed claims is introduced into anotherclaim. For example, any claim that is dependent on another claim can bemodified to include one or more elements, limitations, clauses, ordescriptive terms, found in any other claim that is dependent on thesame base claim. Furthermore, where the claims recite a product (e.g.,an apparatus or device), it is to be understood that methods of usingthe product according to any of the methods disclosed herein, andmethods of making the product, are included within the scope of theinvention, unless otherwise indicated or unless it would be evident toone of ordinary skill in the art that a contradiction or inconsistencywould arise. Methods of treating a subject can include a step ofproviding a subject in need of such treatment (e.g., a subject who has adisease or disorder affecting the respiratory system, such as COPD,and/or who suffers from hyperinflation), a step of diagnosing a subjectas having such disease or disorder, a step of selecting a subject fortreatment, and/or a step of suggesting an apparatus of the invention toa subject or prescribing an apparatus of the invention for a subject orproviding instructions regarding use of the apparatus, e.g.,instructions for using the apparatus for one or more purposes.

Where elements are presented as lists, it is to be understood that eachsubgroup of the elements is also disclosed, and any element(s) can beremoved from the group. The invention provides all such embodiments. Itshould also be understood that, in general, where the invention, oraspects of the invention, is/are referred to as comprising particularelements, features, etc., certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements, features, etc.

The terms “approximately” or “about” in reference to a number generallyinclude numbers that fall within ±10%, in some embodiments ±5%, in someembodiments ±1%, in some embodiments ±0.5% of the number unlessotherwise stated or otherwise evident from the context (except wheresuch number would impermissibly exceed 100% of a possible value). Whereranges are given, endpoints are included. Furthermore, it is to beunderstood that unless otherwise indicated or otherwise evident from thecontext and understanding of one of ordinary skill in the art, valuesthat are expressed as ranges can assume any specific value or subrangewithin the stated ranges in different embodiments of the invention, tothe tenth of the unit of the lower limit of the range, unless thecontext clearly dictates otherwise. In addition, any particularembodiment, aspect, element, feature, etc., of the present invention maybe explicitly excluded from any one or more of the claims.

1. A method of treating a subject comprising: (a) sensing when a subjectis exhaling; and (b) delivering a stimulus to the subject's thorax orabdomen during at least part of the expiratory phase of breathing inresponse to said sensing, so as to assist the subject with exhalation.2. The method of claim 1, wherein performing the method decreases thesubject's end expiratory lung volume (EELV) as compared with thesubject's EELV when unassisted.
 3. The method of claim 1, wherein thesubject suffers from a disorder that impairs exhalation.
 4. The methodof claim 1, wherein the subject suffers from chronic obstructivepulmonary disease (COPD).
 5. The method of claim 1, wherein the subjecthas an abnormally high EELV in the absence of the stimulus.
 6. Themethod of claim 1, wherein the subject suffers from dynamichyperinflation in the absence of the stimulus.
 7. The method of claim 1,wherein step (a) comprises detecting respiratory movement of thesubject's thorax or abdomen.
 8. The method of claim 1, wherein step (a)comprises detecting respiratory movement of the subject's thorax orabdomen using inductive plethysmography.
 9. The method of claim 1,wherein step (a) comprises detecting respiratory movement of thesubject's thorax or abdomen using a strain gauge.
 10. The method ofclaim 1, wherein the sensor is incorporated into an adhesive patchsuitable for placement on the subject's skin.
 11. The method of claim 1,wherein the sensing occurs externally to the subject.
 12. The method ofclaim 1, wherein the stimulus is delivered externally to the subject.13. The method of claim 1, wherein the sensing occurs externally to thesubject and the stimulus is delivered externally to the subject.
 14. Themethod of claim 1, wherein the sensor, device, or both are incorporatedinto a garment or belt.
 15. The method of claim 1, wherein the sensorand the device are incorporated into the same garment or belt.
 16. Themethod of claim 1, wherein step (b) comprises delivering electricalstimulation to one or more muscles of expiration and/or to efferentnerve(s) supplying one or more muscles of expiration, wherein saidstimulus is sufficient to cause contraction of said muscle(s) orincrease the expiratory force generated by said muscle(s).
 17. Themethod of claim 1, wherein step (b) comprises delivering electricalstimulation to one or more abdominal muscles.
 18. The method of claim 1,wherein step (b) comprises delivering electrical stimulation to therectus abdominis muscle.
 19. The method of claim 1, wherein step (b)comprises delivering electrical stimulation to one or more lowerinternal intercostal muscles of the anterior thorax.
 20. The method ofclaim 1, wherein step (b) comprises mechanically compressing thesubject's abdomen or lower anterior thorax. 21-78. (canceled)